Pyrimidine compounds

ABSTRACT

A pyrimidine derivative of formula (I) wherein, for example, R 1  is-(1-6C)alkyl or (3-5C)alkenyl [optionally substituted by a phenyl substituent]; Q 1  and Q 2  are independently selected from phenyl, naphthyl, indanyl and 1,2,3,4-tetrahydronaphthyl; and one or both of Q 1  and Q 2  bears one substituent of formula (Ia) [provided that when present in Q 1  the substituent of formula (Ia) is not adjacent to the —NH-link]; wherein, for example, X is CH 2 , O, S or NH; Y is H or as defined for Z; Z is OH, SH, NH 2 , (1-4C)alkoxy, (1-4C)alkylthio, —NH(1-4C)alkyl, —N[(1-4C)alkyl] 2  or —NH-(3-8C)cycloalkyl; n is 1, 2 or 3; m is 1, 2 or 3; and Q 1  and Q 2  may each optionally bear other substituents selected from halogeno, (1-6C)alkyl, cyano and (2-4C)alkenyl, or a pharmaceutically-acceptable salt, or in-vivo-hydrolysable ester thereof; are useful as anti-cancer agents; and processes for their manufacture and pharmaceutical compositions containing them are described.

This application is the national phase of international applicationPCT/GB99/02797 filed Aug. 24, 1999 which designated the U.S.

The invention relates to pyrimidine derivatives, orpharmaceutically-acceptable salts or in-vivo-hydrolysable estersthereof, which possess anti-cell proliferative (such as anti-cancer)activity and are therefore useful in methods of treatment of the humanor animal body. The invention also relates to processes for themanufacture of said pyrimidine derivatives, to pharmaceuticalcompositions containing them and to their use in the manufacture ofmedicaments for use in the production of an anti-cell proliferation(anti-cancer) effect in a warm-blooded animal such as man.

A family of intracellular proteins called cyclins play a central role inthe cell cycle. The synthesis and degradation of cyclins is tightlycontrolled such that their level of expression fluctuates during thecell cycle. Cyclins bind to cyclin-dependent serine/threonine kinases(CDKs) and this association is essential for CDK (such as CDK1, CDK2,CDK4 and/or CDK6) activity within the cell. Although the precise detailsof how each of these factors combine to regulate CDK activity is poorlyunderstood, the balance between the two dictates whether or not the cellwill progress through the cell cycle.

The recent convergence of oncogene and tumour suppressor gene researchhas identified regulation of entry into the cell cycle as a key controlpoint of mitogenesis in tumours. Moreover, CDKs appear to be downstreamof a number of oncogene signalling pathways. Disregulation of CDKactivity by upregulation of cyclins and/or deletion of endogenousinhibitors appears to be an important axis between mitogenic signallingpathways and proliferation of tumour cells.

Accordingly it has been recognised that an inhibitor of cell cyclekinases, particularly inhibitors of CDK2, CDK4 and/or CDK6 (whichoperate at the S-phase, G1-S and G1-S phase respectively) should be ofvalue as a selective inhibitor of cell proliferation, such as growth ofmammalian cancer cells.

The present invention is based on the discovery that certain4,6-pyrimidine compounds surprisingly inhibit the effects of cell cyclekinases showing selectivity for CDK2, CDK4 and CDK6, and thus possessanti-cancer (anti-cell proliferation) properties. Such properties areexpected to be of value in the treatment of disease states associatedwith aberrant cell cycles and cell proliferation such as cancers (solidtumours and leukemias), fibroproliferative and differentiativedisorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma,haemangioma, acute and chronic nephropathies, atheroma, atherosclerosis,arterial restenosis, autoimmune diseases, acute and chronicinflammation, bone diseases and ocular diseases with retinal vesselproliferation.

According to the invention there is provided a pyrimidine derivative ofthe formula (I)

wherein

R¹ is selected from (1-6C)alkyl [optionally substituted by one or twosubstituents independently selected from halo, amino, (1-4C)alkylamino,di-[(1-4C)alkyl]amino, hydroxy, cyano, (1-4C)alkoxy,(1-4C)alkoxycarbonyl, carbamoyl, —NHCO(1-4C)alkyl, trifluoromethyl,phenylthio, phenoxy, pyridyl, morpholino], benzyl, 2-phenylethyl,(3-5C)alkenyl [optionally substituted by up to three halo substituents,or by one trifluoromethyl substituent, or one phenyl substituent],N-phthalimido-(1-4C)alkyl, (3-5C)alkynyl [optionally substituted by onephenyl substituent] and (3-6C)cycloalkyl-(1-6C)alkyl;

wherein any phenyl or benzyl group in R¹ is optionally substituted by upto three substituents independently selected from halogeno, hydroxy,nitro, amino, (1-3C)alkylamino, di-[(1-3C)alkyl]amino, cyano,trifluoromethyl, (1-3C)alkyl [optionally substituted by 1 or 2substituents independently selected from halogeno, cyano, amino,(1-3C)alkylamino, di-[(1-3C)alkyl]amino, hydroxy and trifluoromethyl],(3-5C)alkenyl [optionally substituted by up to three halo substituents,or by one trifluoromethyl substituent], (3-5C)alkynyl, (1-3C)alkoxy,—SH, —S-(1-3 C)alkyl, carboxy, (1-3 C)alkoxycarbonyl;

Q₁ and Q₂ are independently selected from phenyl, naphthyl, indanyl and1,2,3,4-tetrahydronaphthyl;

and one or both of Q₁ and Q₂ bears on any available carbon atom onesubstituent of the formula (Ia) and Q₂ may optionally bear on anyavailable carbon atom further substituents of the formula (Ia)

 [provided that when present in Q₁ the substituent of formula (Ia) isnot adjacent to the —NH— link];

wherein

X is CH₂, O, S, NH or NRx [wherein Rx is (1-4C)alkyl, optionallysubstituted by one substituent selected from halo, amino, cyano,(1-4C)alkoxy or hydroxy];

Y is H or as defined for Z; Z is OH, SH, NH₂, (1-4C)alkoxy,(1-4C)alkylthio, —NH(1-4C)alkyl, —N[(1-4C)alkyl]₂, —NH-(3-8C)cycloalkyl,pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl [optionally substitutedin the 4-position by (1-4C)alkyl or (1-4C)alkanoyl], morpholino orthiomorpholino; n is 1, 2 or 3; m is 1, 2 or 3;

and Q₁ and Q₂ may each optionally and independently bear on anyavailable carbon atom up to four substituents independently selectedfrom halogeno, hydroxy, thio, nitro, carboxy, cyano, (2-4C)alkenyl[optionally substituted by up to three halo substituents, or by onetrifluoromethyl substituent], (2-4C)alkynyl, (1-5C)alkanoyl,(1-4C)alkoxycarbonyl, (1-6C)alkyl, hydroxy-(1-6C)alkyl,fluoro-(1-4C)alkyl, amino-(1-3C)alkyl, (1-4C)alkylamino-(1-3C)alkyl,di-[(1-4C)alkyl]amino-(1-3C)alkyl, cyano-(1-4C)alkyl,(2-4C)alkanoyloxy-(1-4C)-alkyl, (1-4C)alkoxy-(1-3C)alkyl,carboxy-(1-4C)alkyl, (1-4C)alkoxycarbonyl-(1-4C)alkyl,carbamoyl-(1-4C)alkyl, N-(1-4C)alkylcarbamoyl-(1-4C)alkyl,N,N-di-[(1-4C)alkyl]-carbarmoyl-(1-4C)alkyl, pyrrolidin-1-yl-(1-3C)alkyl, piperidin-1-yl-(1-3C)alkyl, piperazin-1-yl-(1-3C)alkyl,morpholino-(1-3 C)alkyl, thiomorpholino-(1-3C)alkyl, piperazin-1-yl,morpholino, thiomorpholino, (1-4C)alkoxy, cyano-(1-4C)alkoxy,carbamoyl-(1-4C)alkoxy, N-(1-4C)alkylcarbarnoyl-(1-4C)alkoxy,N,N-di-[(1-4C)alkyl]-carbarmoyl-(1-4C)alkoxy, 2-aminoethoxy,2-(1-4C)alkylaminoethoxy, 2-di-[(1-4C)alkyl]aminoethoxy,(1-4C)alkoxycarbonyl-(1-4C)alkoxy, halogeno-(1-4C)alkoxy,2-hydroxyethoxy, (2-4C)alkanoyloxy-(2-4C)alkoxy, 2-(1-4C)alkoxyethoxy,carboxy-(1-4C)alkoxy, (3-5C)alkenyloxy, (3-5C)alkynyloxy,(1-4C)alkylthio, (1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl,hydroxy-(2-4C)alkylthio, hydroxy-(2-4C)alkylsulphinyl,hydroxy-(2-4C)alkylsulphonyl, ureido (H₂N—CO—NH—), (1-4C)alkylNH—CO—NH—,di-[(1-4C)alkyl]- N—CO—NH—, (1-4C)alkylNH—CO—N[(1-4C)alkyl]- ,di-[(1-4C)alkyl]N—CO—N[(1-4C)alkyl]-, carbamoyl,N-[(1-4C)alkyl]carbamoyl, N,N-di-[(1-4C)alkyl]carbamoyl, amino,(1-4C)alkylamino, di-[(1-4C)alkyl]amino, (2-4C)alkanoylamino,

and also independently, or where appropriate in addition to, the aboveoptional substituents, Q₁ and/or Q₂ may optionally bear on any availablecarbon atom up to two further substituents independently selected from(3-8C)cycloalkyl, phenyl-(1-4C)alkyl, phenyl-(1-4C)alkoxy, phenylthio,phenyl, naphtnyl, benzoyl, phenoxy, benzimidazol-2-yl and a 5- or6-membered aromatic heterocycle (linked via a ring carbon atom andcontaining one to three heteroatoms independently selected from oxygen,sulphur and nitrogen); wherein said naphthyl, phenyl, benzoyl, 5- or6-membered aromatic heterocyclic substituents and the phenyl group insaid phenyl-(1-4C)alkyl, phenylthio, phenoxy and phenyl-(1-4C)alkoxysubstituents may optionally bear up to five substituents independentlyselected from halogeno, (1-4C)alkyl and (1-4C)alkoxy; or apharmaceutically-acceptable salt or in-vivo-hydrolysable ester thereof.

A suitable value for a ring substituent when it is a 5- or 6-memberedaromatic heterocycle (linked via a ring carbon atom and containing oneto three heteroatoms independently selected from oxygen, sulphur andnitrogen) is, for example, pyrrole, furan, thiophene, imidazole,oxazole, isoxazole, thiazole, pyridyl, pyridazinyl, pyrimidinyl,pyrazinyl or p-isoxazine.

In this specification the term “alkyl” includes both straight andbranched chain alkyl groups but references to individual alkyl groupssuch as “propyl” are specific for the straight chain version only. Ananalogous convention applies to other generic terms.

Suitable values for the generic radicals (such as in R¹ and insubstituents on Q₁ and Q₂) referred to above include those set outbelow:

when it is halogeno is, for example, fluoro, chloro, bromo and iodo;(2-4C)alkenyl is, for example, vinyl and allyl; when it is (3-5C)alkenylis, for example, allyl or buten-3-yl; when it is (3-5C)alkynyl is, forexample, propyn-2-yl; when it is (2-4C)alkynyl is, for example, ethynyland propyn-2-yl; when it is (3-6C)cycloalkyl-(1-6C)alkyl is, forexample, cyclopropylmethyl; when it is (3-8C)cycloalkyl is, for example,cyclobutyl, cyclopentyl or cyclohexyl; when it is (1-4C)alkanoyl or(1-5C)alkanoyl is, for example, formyl and acetyl;

when it is (1-4C)alkoxycarbonyl is, for example, methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl and tert-butoxycarbonyl; when it is(1-3C)alkyl is, for example, methyl, ethyl, propyl, isopropyl; when itis (1-4C)alkyl is, for example, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl or tert-butyl; when it is (1-6C)alkyl is, forexample, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl or 3-methylbutyl or hexyl; when it is hydroxy-(1-3C)alkyl is,for example, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl and3-hydroxypropyl; when it is hydroxy-(2-4C)alkyl is, for example,2-hydroxyethyl and 3-hydroxypropyl; when it is fluoro-(1-4C)alkyl is,for example, fluoromethyl, difluoromethyl, trifluoromethyl and2-fluoroethyl; when it is amino-(1-3C)alkyl is, for example,aminomethyl, 1-aminoethyl and 2-aminoethyl; when it is(1-4C)alkylamino-(1-3C)-alkyl is, for example, methylaminomethyl,ethylaminomethyl, 1-methylaminoethyl, 2-methylaminoethyl,2-ethylamimoethyl and 3-methylaminopropyl; when it isdi-[(1-4C)alkyl]amino-(1-3C)alkyl is, for example, dimethylaminomethyl,diethylaminomethyl, 1-dimethylaminoethyl, 2-dimethylaminomethyl and3-dimethylaminopropyl; when it is cyano-(1-4C)alkyl is, for examplecyanomethyl, 2-cyanoethyl and 3-cyanopropyl; when it is(2-4C)alkanoyloxy-(1-4C)-alkyl is, for example, acetoxymethyl,propionyloxymethyl, butyryloxymethyl, 2-acetoxyethyl and3-acetoxypropyl; when it is (1-4C)alkoxy-(1-3C)alkyl is, for example,methoxymethyl, ethoxymethyl, 1-methoxyethyl, 2-methoxyethyl,2-ethoxyethyl and 3-methoxypropyl; when it is carboxy-(1-4C)alkyl is,for example carboxymethyl, 1-carboxyethyl, 2-carboxyethyl and3-carboxypropyl; when it is (1-4C)alkoxycarbonyl-(1-4C)alkyl is, forexample, methoxycarbonylmethyl, ethoxycarbonylmethyl,tert-butoxycarbonylmethyl, 1-methoxycarbonylethyl,1-ethoxycarbonylethyl, 2-methoxycarbonylethyl, 2-ethoxycarbonylethyl,3-methoxycarbonylpropyl and 3-ethoxycarbonylpropyl; when it iscarbamoyl-(1-4C)alkyl is, for example carbamoylmethyl, 1-carbamoylethyl,2-carbamoylethyl and 3-carbamoylpropyl; when it isN-(1-4C)alkylcarbamoyl-(1-4C)alkyl is, for example,N-methylcarbamoylmethyl, N-ethylcarbamoylmethyl,N-propylcarbamoylmethyl, 1-(N-methylcarbamoyl)ethyl,1-(N-ethylcarbamoyl)ethyl, 2-(N-methylcarbamoyl)ethyl,2-(N-ethylcarbamoyl)ethyl and 3-(N-methylcarbamoyl)propyl;

when it is N,N-di-[(1-4C)alkyl]-carbamoyl-(1-4C)alkyl is, for example,N,N-dimethylcarbamoylmethyl, N-ethyl-N-methylcarbamoylmethyl,N,N-diethylcarbamoylmethyl, 1-(N-dimethylcarbamoyl)ethyl,1-(N,N-diethylcarbamoyl)ethyl, 2-(N,N-dimethylcarbamoyl)ethyl,2-(N,N-diethylcarbamoyl)ethyl and 3-(N,N-dimethylcarbamoyl)propyl; whenit is pyrrolidin-1-yl-(1-3C)alkyl is, for example, pyrrolidin-1-ylmethyland 2-pyrrolidin-1-ylethyl; when it is piperidin-1-yl-(1-3C)alkyl is,for example, piperidin-1-ylmethyl and 2-piperidin-1-ylethyl; when it ispiperazin-1-yl-(1-3C)alkyl is, for example, piperazin-1-ylmethyl and2-piperazin-1-ylethyl; when it is morpholino-(1-3C)alkyl is, forexample, morpholinomethyl and 2-morpholinoethyl; when it isthiomorpholino-(1-3C)alkyl is, for example, thiomorpholinomethyl and2-thiomorpholinoethyl; when it is (1-4C)alkoxy is, for example, methoxy,ethoxy, propoxy, isopropoxy or butoxy; when it is cyano-(1-4C)alkoxy is,for example, cyanomethoxy, 1-cyanoethoxy, 2-cyanoethoxy and3-cyanopropoxy; when it is carbamoyl-(1-4C)alkoxy is, for example,carbamoylmethoxy, 1-carbamoylethoxy, 2-carbamoylethoxy and3-carbamoylpropoxy; when it is N-(1-4C)alkylcarbamoyl-(1-4C)alkoxy is,for example, N-methylcarbamoylmethoxy, N-ethylcarbamoylmethoxy,2-(N-methylcarbamoyl)ethoxy, 2-(N-ethylcarbamoyl)ethoxy and3-(N-methylcarbarmoyl)propoxy; when it isN,N-di-[(1-4C)alkyl]-carbamoyl-(1-4C)alkoxy is, for example,N,N-dimethylcarbamoylmethoxy, N-ethyl-N-methylcarbamoylmethoxy,N,N-diethylcarbamoylmethoxy, 2-(N,N-dimethylcarbamoyl)ethoxy,2-(N,N-diethylcarbamoyl)ethoxy and 3-(N,N-dimethylcarbamoyl)propoxy;when it is 2-(1-4C)alkylaminoethoxy is, for example,2-(methylamino)ethoxy, 2-(ethylamino)ethoxy and 2-(propylamino)ethoxy;when it is 2-di-[(1-4C)alkyl]aminoethoxy is, for example,2-(dimethylamino)ethoxy, 2-(N-ethyl-N-methylamino)ethoxy,2-(diethylamino)ethoxy and 2-(dipropylamino)ethoxy; when it is(1-4C)alkoxycarbonyl-(1-4C)alkoxy is, for example,methoxycarbonylmethoxy, ethoxycarbonylmethoxy, 1-methoxycarbonylethoxy,2-methoxycarbonylethoxy, 2-ethoxycarbonylethoxy and3-methoxycarbonylpropoxy; when it is halogeno-(1-4C)alkoxy is, forexample, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy,2-chloroethoxy, 2-bromoethoxy, 3-fluoropropoxy, 3-chloropropoxy and2-chloro-2,1,1-trifluoroethoxy; when it is(2-4C)alkanoyloxy-(2-4C)alkoxy is, for example, 2-acetoxyethoxy,2-propionyloxyethoxy, 2-butyryloxyethoxy and 3-acetoxypropoxy; when itis 2-(1-4C)alkoxyethoxy is, for example, 2-methoxyethoxy,2-ethoxyethoxy; when it is carboxy-(1-4C)alkoxy is, for example,carboxymethoxy, 1-carboxyethoxy, 2-carboxyethoxy and 3-carboxypropoxy;when it is (3-5C)alkenyloxy is, for example, allyloxy; when it is(3-5C)alkynyloxy is, for example, propynyloxy; when it is(1-4C)alkylthio is, for example, methylthio, ethylthio or propylthio;when it is (1-4C)alkyylsulphinyl is, for example, methylsulphinyl,ethylsulphinyl or propylsulphinyl; when it is (1-4C)alkylsulphonyl is,for example, methylsulphonyl, ethylsulphonyl or propylsulphonyl; when itis N-(1-4C)alkylcarbamoyl is, for example N-methylcarbamoyl,N-ethylcarbamoyl and N-propylcarbamoyl; when it isN,N-di-[(1-4C)alkyl]-carbamoyl is, for example N,N-dimethylcarbamoyl,N-ethyl-N-methylcarbamoyl and N,N-diethylcarbamoyl; when it is(1-4C)alkylamino or (1-3C)alkylamino is, for example, methylamino,ethylamino or propylamino; when it is di-[(1-4C)alkyl]amino ordi-[(1-3C)alkyl]amino is, for example, dimethylamino,N-ethyl-N-methylamino, diethylamino, N-methyl-N-propylamino ordipropylamino; when it is (2-4C)alkanoylamino is, for example,acetamido, propionamido or butyramido; when it is phenyl-(1-4C)alkyl is,for example benzyl or 2-phenylethyl; when it is phenyl-(1-4C)alkoxy is,for example benzyloxy; when it is —NHCO(1-4C)alkyl is, for exampleacetamido; when it is N-phthalimido-(1-4C)alkyl is, for example2-(N-phthalimido)ethyl or 3-(N-phthalimido)propyl.

A suitable pharmaceutically-acceptable salt of a pyrimidine derivativeof the invention is, for example, an acid-addition salt of a pyrimidinederivative of the invention which is sufficiently basic, for example, anacid-addition salt with, for example, an inorganic or organic acid, forexample hydrochloric, hydrobromic, sulphuric, phosphoric,trifluoroacetic, citric or maleic acid. In addition a suitablepharmaceutically-acceptable salt of a pyrimidine derivative of theinvention which is sufficiently acidic is an alkali metal salt, forexample a sodium or potassium salt, an alkaline earth metal salt, forexample a calcium or magnesium salt, an ammonium salt or a salt with anorganic base which affords a physiologically-acceptable cation, forexample a salt with methylamine, dimethylamine, trimethylamine,piperidine, morpholine, tris-(2-hydroxyethyl)amine, N-methylpiperidine,N-ethylpiperidine, procaine, dibenzylamine, N,N-dibenzylethylamine,N-methyl deglucamine and amino acids such as lysine. There may be morethan one cation or anion depending on the number of charged functionsand the valency of the cations or anions. A preferredpharmaceutically-acceptable salt is the sodium salt.

However, to facilitate isolation of the salt during preparation, saltswhich are less soluble in the chosen solvent may be preferred whetherpharmaceutically-acceptable or not.

In another embodiment there is provided a compound of formula (I)wherein

R¹ is selected from (1-6C)alkyl [optionally substituted by one or twosubstituents independently selected from halo, amino, (1-4C)alkylamino,di-[(1-4C)alkyl]amino, hydroxy, cyano, (1-4C)alkoxy,(1-4C)alkoxycarbonyl, carbamoyl, —NHCO(1-4C)alkyl, trifluoromethyl,phenylthio, phenoxy], benzyl, (3-5C)alkenyl [optionally substituted byup to three halo substituents, or by one trifluoromethyl substituent, orone phenyl substituent], N-phthalimido-(1-4C)alkyl, (3-5C)alkynyl and(3-6C)cycloalkyl-(1-6C)alkyl;

wherein any phenyl or benzyl group in R¹ is optionally substituted by upto three substituents independently selected from halogeno, hydroxy,nitro, amino, (1-3C)alkylamino, di-[(1-3C)alkyl]amino, cyano,trifluoromethyl, (1-3C)alkyl [optionally substituted by 1 or 2substituents independently selected from halogeno, cyano, amino,(1-3C)alkylamino, di-[(1-3C)alkyl]amino, hydroxy and trifluoromethyl],(3-5C)alkenyl [optionally substituted by up to three halo substituents,or by one trifluoromethyl substituent], (3-5C)alkynyl, (1-3 C)alkoxy,—SH, —S-(1-3 C)alkyl, carboxy, (1-3C)alkoxycarbonyl;

Q₁ and Q₂ are both phenyl;

and one or both of Q₁ and Q₂ bears on any available carbon atom onesubstituent of the formula (Ia) and Q₂ may bear on any available carbonatom further substituents of the formula (Ia) [provided that whenpresent in Q₁ the substituent of formula (Ia) is not adjacent to the—NH— link];

wherein X is CH₂, O, NH or S; Y is H or as defined for Z; Z is OH, SH,NH₂, (1-4C)alkoxy, (1-4C)alkylthio, —NH(1-4C)alkyl, [N[(1-4C)alkyl]₂,pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, morpholino orthiomorpholino; n is 1, 2 or 3; n is 1, 2 or 3;

and Q₁ and Q₂ may each optionally bear on any available carbon atom upto four substituents independently selected from halogeno, hydroxy,thio, nitro, carboxy, cyano, (2-4C)alkenyl [optionally substituted by upto three halo substituents, or by one trifluoromethyl substituent],(2-4C)alkynyl, (1-5C)alkanoyl, (1-4C)alkoxycarbonyl, (1-6C)alkyl,hydroxy-(1-3C)alkyl, fluoro-(1-4C)alkyl, amino-(1-3C)alkyl,(1-4C)alkylamino-(1-3 C)alkyl, di-[(1-4C)alkyl]amino-(1-3C)alkyl,cyano-(1-4C)alkyl, (2-4C)alkanoyloxy-(1-4C)-alkyl,(1-4C)alkoxy-(1-3C)alkyl, carboxy-(1-4C)alkyl,(1-4C)alkoxycarbonyl-(1-4C)alkyl, carbamoyl-(1-4C)alkyl,N-(1-4C)alkylcarbamoyl-(1-4C)alkyl,N,N-di-d[(1-4C)alkyl]-carbamoyl-(1-4C)alkyl, pyrrolidin-1-yl-(1-3C)alkyl, piperidin-1-yl-(1-3C)alkyl, piperazin-1-yl-(1-3C)alkyl,morpholino-(1-3C)alkyl, thiomorpholino-(1-3C)alkyl, piperazin-1-yl,morpholino, thiomorpholino, (1-4C)alkoxy, cyano-(1-4C)alkoxy,carbamoyl-(1-4C)alkoxy, N-(1-4C)alkylcarbamoyl-(1-4C)alkoxy,N,N-di-[(1-4C)alkyl]-carbamoyl-(1-4C)alkoxy, 2-aminoethoxy,2-(1-4C)alkylaminoethoxy, 2-di-[(1-4C)alkyl]aminoethoxy,(1-4C)alkoxycarbonyl-(1-4C)alkoxy, halogeno-(1-4C)alkoxy,2-hydroxyethoxy, (2-4C)alkanoyloxy-(2-4C)alkoxy, 2-(1-4C)alkoxyethoxy,carboxy-(1-4C)alkoxy, (3-5C)alkenyloxy, (3-5C)alkynyloxy,(1-4C)alkylthio, (1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl, ureido(H₂N—CO—NH—), (1-4C)alkylNH—CO—NH—, di-[(1-4C)alkyl]-N—CO—NH—,(1-4C)alkylNH—CO—N[(1-4C)alkyl]-, di-((1-4C)alkyl]N—CO—N[(1-4C)alkyl]-,carbamoyl, N-[(1-4C)alkyl]carbamoyl, N,N-di-[(1-4C)alkyl]carbamoyl,amino, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, (2-4C)alkanoylamino,

and also independently, or in addition to the above substituents, Q₁and/or Q₂ may optionally bear on any available carbon atom up to twofurther substituents independently selected from phenyl-(1-4C)alkyl,phenyl-(1-4C)alkoxy, phenyl, naphthyl, benzoyl and a 5- or 6-memberedaromatic heterocycle (linked via a ring carbon atom and containing oneto three heteroatoms independently selected from oxygen, sulphur andnitrogen); wherein said naphthyl, phenyl, benzoyl, 5- or 6-memberedaromatic heterocyclic substituents and the phenyl group in saidphenyl-(1-4C)alkyl and phenyl-(1-4C)alkoxy substituents may optionallybear one or two substituents independently selected from halogeno,(1-4C)alkyl and (1-4C)alkoxy; or a pharmaceutically-acceptable salt orin-vivo-hydrolysable ester thereof.

In a further embodiment there is provided a compound of formula (I)wherein

R¹ is selected from (1-6C)alkyl [optionally substituted by one or twosubstituents independently selected from halo, amino, (1-4C)alkylamino,di-(1-4C)alkylamino, hydroxy, cyano, (1-4C)alkoxy, (1-4C)alkoxycarbonyland carbamoyl], benzyl, (2-4C)alkenyl, (2-5C)alkynyl and(3-6C)cycloalkyl-(1-6C)alkyl;

Q₁ and Q₂ are both phenyl;

and one or both of Q₁ and Q₂ bears on any available carbon atom that isnot adjacent to the —NH— or —NR¹— link one or more substituents of theformula (Ia)

wherein X is CH₂, O, NH or S; Y is H or as defined for Z; Z is OH, SH,NH₂, (1-4C)alkoxy, (1-4C)alkylthio, —NH(1-4C)alkyl, —N [(1-4C)alkyl]₂,pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, morpholino orthiomorpholino; n is 1, 2 or 3; m is 1, 2 or 3;

and Q₁ and Q₂ may each optionally bear on any available carbon atom upto four substituents independently selected from halogeno, hydroxy, oxo,thioxo, nitro, carboxy, cyano, (2-4C)alkenyl, (2-4C)alkynyl,(1-5C)alkanoyl, (1-4C)alkoxycarbonyl, (1-4C)alkyl, hydroxy-(1-3 C)alkyl,fluoro-(1-4C)alkyl, amino-(1-3 C)alkyl, (1-4C)alkylamino-(1-3C)alkyl,di-[(1-4C)alkyl]amino-(1-3C)alkyl, cyano-(1-4C)alkyl,(2-4C)alkanoyloxy-(1-4C)-alkyl, (1-4C)alkoxy-(1-3C)alkyl,carboxy-(1-4C)alkyl, (1-4C)alkoxycarbonyl-(1-4C)alkyl,carbamoyl-(1-4C)alkyl, N-(1-4C)alkylcarbamoyl-(1-4C)alkyl,N,N-di-[(1-4C)alkyl]-carbamoyl-(1-4C)alkyl, pyrrolidin-1-yl-(1-3C)alkyl, piperidin-1-yl-(1-3 C)alkyl, piperazin-1-yl-(1-3C)alkyl,morpholino-(1-3 C)alkyl, thiomorpholino-(1-3C)alkyl, (1-4C)alkoxy,cyano-(1-4C)alkoxy, carbamoyl-(1-4C)alkoxy,N-(1-4C)alkytcarbamoyl-(1-4C)alkoxy,N,N-di-[(1-4C)alkyl]-carbamoyl-(1-4C)alkoxy, 2-aminoethoxy,2-(1-4C)alkylaminoethoxy, 2-di-[(1-4C)alkyl]aminoethoxy,(1-4C)alkoxycarbonyl-(1-4C)alkoxy, halogeno-(1-4C)alkoxy,2-hydroxyethoxy, (2-4C)alkanoyloxy-(2-4C)alkoxy, 2-(1-4C)alkoxyethoxy,carboxy-(1-4C)alkoxy, (2-4C)alkenyloxy, (2-4C)alkynyloxy,(1-4C)alkylthio, (1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl, ureido,carbamoyl, N-[(1-4C)alkyl]carbamoyl, N,N-di-[(1-4C)alkyl]carbamoyl,amino, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, (2-4C)alkanoylamino,phenyl-(1-4C)alkyl, phenyl-(1-4C)alkoxy, phenyl, naphthyl, benzoyl and a5- or 6-membered aromatic heterocycle (linked via a ring carbon atom andcontaining one to three heteroatoms independently selected from oxygen,sulphur and nitrogen); wherein said naphthyl, phenyl, benzoyl, 5- or6-membered aromatic heterocyclic substituents and the phenyl group insaid phenyl-(1-4C)alkyl and phenyl-(1-4C)alkoxy substituents mayoptionally bear one or two substituents independently selected fromhalogeno, (1-4C)alkyl and (1-4C)alkoxy; or a pharmaceutically-acceptablesalt or in-vivo-hydrolysable ester thereof.

The compounds of the formula (I) may be administered in the form of apro-drug which is broken down in the human or animal body to give acompound of the formula (I). A prodrug may be used to alter or improvethe physical and/or pharmacokinetic profile of the parent compound andcan be formed when the parent compound contains a suitable group orsubstituent which can be derivatised to form a prodrug. Examples ofpro-drugs include in-vivo hydrolysable esters of a compound of theformula (I) or a pharmaceutically-acceptable salt thereof.

Various forms of prodrugs are known in the art, for examples see:

a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) andMethods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al.(Academic Press, 1985);

b) A Textbook of Drug Design and Development, edited byKrogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application ofProdrugs”, by H. Bundgaard p. 113-191 (1991);

c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);

d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285(1988); and

e) N. Kakeya, et al., Chem Pharm Bull, 32, 692 (1984).

An in-vivo hydrolysable ester of a compound of the formula (I) or apharmaceutically-acceptable salt thereof containing carboxy or hydroxygroup is, for example, a pharmaceutically-acceptable ester which ishydrolysed in the human or animal body to produce the parent acid oralcohol. Suitable pharmaceutically-acceptable esters for carboxy include(1-6C)alkoxymethyl esters for example methoxymethyl,(1-6C)alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidylesters, (3-8C)cycloalkoxycarbonyloxy-(1-6C)alkyl esters for example1-cyclohexylcarbonyloxyethyl; 1,3-dioxolan-2-onylmethyl esters forexample 5-methyl-1,3-dioxoan-ylmethyl; and (1-6C)alkoxycarbonyloxyethylesters for example 1-methoxycarbonyloxyethyl and may be formed at anycarboxy group in the compounds of this invention.

An in-vivo hydrolysable ester of a compound of the formula (I) or apharmaceutically-acceptable salt thereof containing a hydroxy group orgroups includes inorganic esters such as phosphate esters (includingphosphoramidic cyclic esters) and α-acyloxyalkyl ethers and relatedcompounds which as a result of the in-vivo hydrolysis of the esterbreakdown to give the parent hydroxy group/s. Examples of α-acyloxyalkylethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. Aselection of in-vivo hydrolysable ester forming groups for hydroxyinclude (1-10C)alkanoyl, benzoyl, phenylacetyl and substituted benzoyland phenylacetyl, (1-10C)alkoxycarbonyl (to give alkyl carbonateesters), di-(1-4C)alkylcarbamoyl andN-(di-(1-4C)alkylaminoethyl)-N-(1-4C)alkylcarbamoyl (to givecarbamates), di-(1-4C)alkylaminoacetyl and carboxyacetyl. Examples ofsubstituents on benzoyl include chloromethyl, aminomethyl,(1-4C)alkylaminomethyl and di-((1-4C)alkyl)aminomethyl, and morpholinoor piperazino linked from a ring nitrogen atom via a methylene linkinggroup to the 3- or 4-position of the benzoyl ring.

Certain suitable in-vivo hydrolysable esters of a compound of theformula (I) are described within the definitions listed in thisspecification. Further suitable in-vivo hydrolysable esters of acompound of the formula (I) are described as follows. For example, a1,2-diol may be cyclised to form a cyclic ester of formula (PD1) or apyrophosphate of formula (PD2):

Esters of compounds of formula (I) wherein the HO— function/s in (PD1)and (PD2) are protected by (1-4C)alkyl, phenyl or benzyl are usefulintermediates for the preparation of such pro-drugs.

Further in-vivo hydrolysable esters include phosphoramidic esters, andalso compounds of formula (I) in which any free hydroxy groupindependently forms a phosphoryl (npd is 1) or phosphiryl (npd is 0)ester of the formula (PD3):

Useful intermediates for the preparation of such esters includecompounds containing a group/s of formula (PD3) in which either or bothof the —OH groups in (PD3) is independently protected by (1-4C)alkyl,phenyl or phenyl-(1-4C)alkyl (such phenyl groups being optionallysubstituted by 1 or 2 groups independently selected from (1-4C)alkyl,nitro, halo and (1-4C)alkoxy).

Thus, prodrugs containing groups such as (PD1), (PD2) and (PD3) may beprepared by reaction of a compound of formula (I) containing suitablehydroxy group/s with a suitably protected phosphorylating agent (forexample, containing a chloro or dialkylamrino leaving group), followedby oxidation (if necessary) and deprotection.

When a compound of formula (I) contains a number of free hydroxy group,those groups not being converted into a prodrug functionality may beprotected (for example, using a t-butyl-trimethylsilyl group), and laterdeprotected. Also, enzymatic methods may be used to selectivelyphosphorylate or dephosphorylate alcohol functionalities.

Where pharmaceutically-acceptable salts of an in-vivo hydrolysable estermay be formed this is achieved by conventional techniques. Thus, forexample, compounds containing a group of formula (PD1), (PD2) and/or(PD3) may ionise (partially or fully) to form salts with an appropriatenumber of counter-ions. Thus, by way of example, if an in-vivohydrolysable ester prodrug of a compound of formula (I) contains two(PD3) groups, there are four HO—P— functionalities present in theoverall molecule, each of which may form an appropriate salt (i.e. theoverall molecule may form, for example, a mono-, di-, tri- ortetra-sodium salt).

Some compounds of the formula (I) may have chiral centres and/orgeometric isomeric centres (E- and Z-isomers), and it is to beunderstood that the invention encompasses all such optical,diastereo-isomers and geometric isomers, and mixtures thereof, thatpossess CDK inhibitory activity.

The invention relates to any and all tautomeric forms of the compoundsof the formula (I) that possess CDK inhibitory activity.

It is also to be understood that certain compounds of the formula (I)can exist in solvated as well as unsolvated forms such as, for example,hydrated forms. It is to be understood that the invention encompassesall such solvated forms which possess CDK inhibitory activity.

Particular preferred compounds of the invention comprise a pyrimidinederivative of the formula (I), or pharmaceutically-acceptable salt orin-vivo hydrolysable ester thereof, wherein R¹, Q₁, Q₂, X, Y, Z, m and nhave any of the meanings defined hereinbefore, or any of the followingvalues. Such values may be used where appropriate with any of thedefinitions, claims or embodiments defined hereinbefore or hereinafter.

(a0) When Q₁ or Q₂ is indanyl or 1,2,3,4-tetrahydronaphthyl, it islinked via the unsaturated ring; preferably Q₁ and/or Q₂ are (both)phenyl;

(a1) In another embodiment R¹ is preferably benzyl, (3-5C)alkynyl(especially propyn-2-yl), (3-6C)cycloalkyl-(1-6C)alkyl (especiallycyclopropylmethyl), (1-4C)alkyl [optionally substituted by one or twosubstituents selected from hydroxyy, amino, halo, trifluoromethyl andcyano] or (3-5C)alkenyl substituted by one to three halo groups;

(b) R¹ is preferably benzyl, (3-5C)alkynyl (especially propyn-2-yl),(3-6C)cycloalkyl-(1-6C)alkyl (especially cyclopropylmethyl), (1-4C)alkyl[optionally substituted by one substituent selected from hydroxy, amino,halo, trifluoromethyl and cyano] or (3-5C)alkenyl substituted by onehalo group;

(c) R¹ is more preferably (3-5C)alkynyl (especially propyn-2-yl) or(1-4C)alkyl [optionally substituted by trifluoromethyl or cyano] or(3-5C)alkenyl substituted by one bromo group;

(d) R¹ is most preferably propyn-2-yl, (1-4C)alkyl substituted by onetrifluoromethyl or one cyano group (especially cyanomethyl or2-cyanoethyl) or (3-5C)alkenyl substituted by one bromo group(especially —CH₂CH═CHBr);

(e) R¹ is most especially preferred as —CH₂CH═CHBr, —CH₂CH₂CH₂CF₃ or—CH₂CH═CH-phenyl;

(e1) In another embodiment R¹ is preferred as propyn-2-yl, cyanomethyl,2-cyanoethyl, —CH₂CH═CHBr or —CH₂CH₂CH₂CF₃ (especially —CH₂CH₂CH₂CF₃);

(f) In one embodiment Z is preferably —NH(1-4C)alkyl, —N[(1-4C)alkyl]₂,—NH-(3-8C)cycloalkyl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl[optionally substituted in the 4-position by (1-4C)alkyl or(1-4C)alkanoyl], morpholino or thiomorpholino; or alternatively Z isNH₂;

(f1) In one embodiment Y is preferably H, OH, SH, NH₂, (1-4C)alkoxy,(1-4C)alkylthio, —NH(1-4C)alkyl, —N[(1-4C)alkyl]₂or—NH-(3-8C)cycloalkyl; especially H or OH;

(f2) In one embodiment X is preferably O or NH or NRx; least preferredis X as S;

(f3) Preferably n+m is less than 5;

(f3) Preferably in the substituent of formula (Ia) X is O, Y is H or OHand Z is —NH(1-4C)alkyl, —N[(1-4C)alkyl]₂ or —NH-(3-8C)cycloalkyl;preferably n is 1 and m is 1;

(f4) In another embodiment in the substituent of formula (Ia) X is O, Yis OH and Z is —N[(1-4C)alkyl]₂; preferably n is 1 and m is 1;

(g) Most preferably the substituent of formula (Ia) is3-dimethylamino-2-hydroxypropoxy;

(h) Preferably there is one substituent of formula (Ia), and thissubstituent is in ring Q₁ (i.e a ring linked via —NH—);

(i) When the substituent of formula (Ia) is in Q₁ it must be in eitherthe para- or meta-position relative to the —NH—, preferably in thepara-position;

(j) Preferably Q₁ bears no further substituents (other than (Ia));preferable further substituents for Q₂include halo, hydroxy-(1-3C)alkyl,fluoro-(1-4C)alkyl (especially trifluoromethyl), morpholino and(1-4C)alkyl (especially methyl);

(k) More preferable further substituents for Q₂ include halo, morpholinoand (1-4C)alkyl (especially methyl);

(l) Preferably the ring Q₁ or Q₂ not bearing the substituent of formula(Ia) is substituted by one or two further substituents, preferably halo,morpholino and/or (1-4C)alkyl (especially methyl);

(m) Most preferably the ring Q₁ bears the substituent of formula (Ia)and Q₂ is substituted by one or two further substituents, selectedpreferably from halo, hydroxy-(1-3 C)alkyl, fluoro-(1-4C)alkyl(especially trifluoromethyl), morpholino and (1-4C)alkyl (especiallymethyl).

A preferred compound of the invention is a pyrimidine derivative of theformula (I), or pharmaceutically-acceptable salt or in-vivo hydrolysableester thereof as claimed in any of claims 1 to 5 and wherein (i) Q₂ doesnot bear any optional further substituents of formula (Ia) and/or (ii)there is one substituent of formula (Ia), borne by Q₁ and/or (iii) inclaims 1 or 2 Q₁ does not bear any of the additional two furthersubstituents that are listed.

A further preferred compound of the invention is a pyrimidine derivativeof the formula (I), or pharmaceutically-acceptable salt or in-vivohydrolysable ester thereof, wherein:

Q₁ and Q₂ are both phenyl;

R¹ is (1-4C)alkyl substituted by one cyano group (especiallycyanomethyl);

or alternatively R¹ is —CH₂CH═CHBr or —CH₂CH₂CH₂CF₃ (especially—CH₂CH₂CH₂CF₃) or —CH₂CH═CH-phenyl;

Q₁ bears one substituent of formula (Ia) (especially3-dimethylamino-2-hydroxypropoxy), preferably in the para-position;

Q₂ bears one or two substituents independently selected from halo,morpholino and (1-4C)alkyl (especially methyl).

A specific preferred compound of the invention is the followingpyrimidine derivative of the formula (I):

4-{4-[3-(N,N-Dimethyl)amino-2-hydroxy-propoxy]anilino}-6-(N-cyanomethyl-2-bromo-4-methylanilino)pyrimidine;

4-{4-[3-(N,N-Dimethyl)amino-2-hydroxy-propoxy]anilin}-6-(N-cyanomethyl-2-chloro-5-methylanilino)pyrimidine;

4-{4-[3-(N,N-Dimethyl)amino-2-hydroxy-propoxy]anilino}-6-(N-(3-phenylprop-2-enyl)-2-bromo-4-methylanilino)pyrimidine;or pharmaceutically-acceptable salt or in-vivo hydrolysable esterthereof.

Other specific preferred compounds of the invention are the pyrimidinederivatives of the formula (I), described in Examples 6, 10, 19 and 20,or pharmaceutically-acceptable salts or in-vivo hydrolysable estersthereof.

Process Section

A pyrimidine derivative of the formula (I), or apharmaceutically-acceptable salt or an in vivo hydrolysable esterthereof, may be prepared by any process known to be applicable to thepreparation of chemically-related compounds. Such processes, when usedto prepare a pyrimidine derivative of the formula (I), or apharmaceutically-acceptable salt or an in vivo hydrolysable esterthereof, are provided as a further feature of the invention and areillustrated by the following representative examples in which, unlessotherwise stated R¹, Q₁, Q₂, X, Y, Z, m and n have any of the meaningsdefined hereinbefore for a pyrimidine derivative of the formula (I) andunless another substituent is drawn on ring Q₁ or Q₂ the ring may bearany of the substituents described hereinbefore (optionally protected asnecessary). Where a substituent is drawn on ring Q₁, this includes(unless stated otherwise) the possibilities of the substituent/s beingon ring Q₂ in addition to, or instead of the substituent being on ringQ₁. Where X is defined in this process section as NH it is to beunderstood that this also includes the possibility of X as NRx.

Necessary starting materials may be obtained by standard procedures oforganic chemistry (see, for example Advanced Organic Chemistry(Wiley-interscience), Jerry March—also useful for general guidance onreaction conditions and reagents). The preparation of such startingmaterials is described within the accompanying non-limiting processesand Examples. Alternatively necessary starting materials are obtainableby analogous procedures to those illustrated which are within theordinary skill of an organic chemist.

Thus, as a further feature of the invention there are provided thefollowing processes which comprises of:

a) reacting a pyrimidine of formula (II):

 wherein L is a displaceable group as defined below, with a compound offormula (III):

b) reaction of a pyrimidine of formula (IV):

 wherein L is a displaceable group as defined below, with a compound offormula (V):

c) reacting a pyrimidine of formula (VI):

 with a compound of formula (VII)

R¹—L  (VII)

wherein L is a displaceable group as defined below;

d) for compounds of formula (I) where n=1, 2 or 3; m=1 and Y is OH, NH,or SH, reaction of a 3-membered heteroalkyl ring of formula (VIII):

 wherein A is O, S or NH;

with a nucleophile of formula (IX):

Z—D  (IX)

 wherein D is H or a suitable counter-ion;

e) for compounds of formula (I) where X is oxygen, by reaction of analcohol of formula (X):

 with an alcohol of formula (XI):

f) for compounds of formula (I) wherein X is CH₂, O, NH or S; Y is OHand In is 2 or 3;

reaction of a compound of formula (XII):

 wherein —OLg is a leaving group such as mesylate or tosylate; with anucleophile of formula Z—D (IX) wherein D is H or a suitablecounter-ion;

g) for compounds of formula (I) wherein X is CH₂, O, NH or S; Y is H; nis 1, 2 or 3 and m is 1, 2 or 3:

reaction of a compound of formula (XIII):

 wherein —OLg is a leaving group such as mesylate or tosylate; with anucleophile of formula Z—D (IX) wherein D is H or a suitablecounter-ion;

h) for compounds of formula (I) wherein X is O, NH or S; Y is H; n is 1,2 or 3 and m is 1, 2 or 3; reaction of a compound of formula (XIV) witha compound of formula (XV):

 or

i) for compounds of formula (I) in which Z is SH, by conversion of athioacetate group in a corresponding compound; and thereafter ifnecessary:

(i) converting a compound of the formula (I) into another compound ofthe formula (I);

(ii) removing any protecting groups;

(iii) forming a pharmaceutically acceptable salt or in vivo hydrolysableester.

L is a displaceable group, suitable values for L are for example, ahalogeno or sulphonyloxy group, for example a chloro, bromo,methanesulphonyloxy or toluene-4-sulphonyloxy group.

D is hydrogen or a counter-ion. When D is a counter-ion, suitable valuesfor D include sodium and potassium.

Specific reaction conditions for the above reactions are as follows:

Process a)

Pyrimidines of formula (II) and compounds of formula (III) may bereacted together

i) optionally in the presence of a suitable acid, for example aninorganic acid such as hydrochloric acid or sulphuric acid, or anorganic acid such as acetic acid or formic acid. The reaction ispreferably carried out in a suitable inert solvent or diluent, forexample dichloromethane (DCM), acetonitrile, butanol, tetramethylenesulphone, tetrahydrofuran, 1,2-dimethoxyethane, N,N-dimethylformamide,N,N-dimethylacetamide or N-methylpyrrolidin-2-one, and at a temperaturein the range, for example, 0° to 150° C., conveniently at or near refluxtemperature; or

ii) under standard Buchwald conditions (for example see J. Am. Chem.Soc., 118, 7215; J. Am. Chem. Soc., 119, 8451; J. Org. Chem., 62, 1568and 6066) for example in the presence of palladium acetate, in asuitable solvent for example an aromatic solvent such as toluene,benzene or xylene, with a suitable base for example an inorganic basesuch as caesium carbonate or an organic base such aspotassium-t-butoxide, in the presence of a suitable ligand such as2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and at a temperature in therange of 25 to 80° C.

Pyrimidines of the formula (II) may be prepared according to thefollowing scheme:

Compounds of formula (III) are commercially available or are prepared byprocesses known in the art.

Process b)

Pyrimidines of formula (IV) and compounds of formula (V) may be reactedtogether

i) in the presence of a suitable solvent for example a ketone such asacetone or an alcohol such as ethanol or butanol or an aromatichydrocarbon such as toluene or N-methyl pyrrolidine, or a solvent suchas tetramethylene sulphone, optionally in the presence of a suitableacid such as those defined above and at a temperature in the range of 0°C. to reflux, preferably reflux; or

ii) under standard Buchwald conditions as described above,

Pyrimidines of formula (IV) are prepared according to the followingscheme:

wherein L is a displaceable group as defined above.

The compounds of formula (V) are commercially available or are preparedby processes known in the art.

Process c)

Pyrimidines of formula (VI) and compounds of formula (VII) are reactedtogether in the presence of a suitable base such as sodium hydride orpotassium carbonate or potassium tert-butoxide and a suitable solventsuch as N,N-dimethylformamide, dimethyl sulfoxide or tetrahydrofuran ata temperature in the range of −20° to 110° C., preferably −20° to 60° C.

Compounds of formula (VI) may be prepared according to the followingscheme:

Process d)

Three membered heteroalkyl rings of formula (VIII) and nucleophiles offormula (IX) are reacted together at a temperature in the range of 20°to 100° C., preferably 20° to 50° C., optionally in the presence of asuitable solvent, for example N,N-dimethylformamide, dimethyl sulfoxideor tetrahydrofuran.

Compounds formula (VIII) may be prepared according to the followingschemes:

Scheme I) for compounds of formula (VIII) where A is O, and X is notcarbon:

The conversion of (VIIIB) to (VIII) may also be achieved by reactionwith Br—(CH₂)_(n)—CHO, or an equivalent ester, in DMF and the presenceof a base, followed by reaction with a sulfur ylide such as (Me₂SOCH₂)in an inert solvent such as THF (see Scheme V); followed by reactionwith R¹—L.

Scheme II) for compounds of formula (VIII) where A is NH, and X is notcarbon:

(for PhINTs see, for example. Tet.Let., 1997, 38 (39), 6897-6900;compounds of formula (VIIIC) may also be oxidised to the epoxide usingconditions similar to that in Scheme IV) below);

Scheme III) for compounds of formula (VIII) where A is S, and X is notcarbon:

(for example see Synlett. 1994, 267-268);

Scheme IV) For compounds of formula (VIII) where X is carbon

 wherein R³ together with the —COO— group to which it is attached formsan ester moiety, for example a methyl ester or an ethyl ester.

Scheme V) For compounds of formula (VIII) wherein X is CH₂, O, NH or S;Y is OH; n is 1, 2 or 3 and m is 1:

(XB) is reacted with (IVC) (see Scheme I) and then R¹—L to give (VIII).

An equivalent ester of (XA) may also be used. See also Russ.Chem. Rev.47, 975-990, 1978.

Compounds of formula (VII), (IX), (VIIIA) and (VIIID) are commerciallyavailable or are prepared by processes known in the art.

Process e)

Alcohols of formula (X) and (XI) can be reacted together under standardMitsunobu conditions. For example in the presence of diethylazodicarboxylate and triphenyl phosphine, in a suitable solvent such asdichloromethane, toluene or tetrahydrofuran, and at a temperature in therange of 0° to 80° C., preferably in the range of 20° to 60° C.

Alcohols of formula (X) are made according to the process in Scheme I)above for the synthesis of intermediate (VIIIB) (where X is oxygen).

Alcohols of formula (XI) are commercially available or are made byprocesses known in the art.

In a process analogous to process e), compounds in which X is S may beprepared by reaction of a compound of formula (X) in which the hydroxygroup is —SH, with a compound of formula (XI) in which the hyrdoxy groupis a leaving group such as mesylate or tosylate.

Process f)

Compounds of formula (XII) wherein X is CH₂, O, NH or S; Y is OH and mis 2 or 3 and nucleophiles of formula (IX) are reacted together at atemperature in the range of 20° to 100° C., preferably 20° to 50° C.,optionally in the presence of a suitable solvent, for exampleN,N-dimethylformamide, dimethyl sulphoxide or tetrahydrofuran,andoptionally in the presence of a suitable base, such as potassiumcarbonate.

Compounds of formula (XII) are prepared according to the followingscheme (m is 2 or 3):

The steps 1) and 2) in the final step may be reversed. A suitable basefor step 2) is triethylamine.

Compounds of formula (XIIA) and (IX) are commercially available or areprepared by processes known in the art. For example, compounds offormula (XIIA) in which X is NH, O or S may be prepared by reaction of acompound of formula (VIIIA) with a suitable haloaldehyde or equivalentester under standard conditions for such reactions.

Process g)

Compounds of formula (XIII) and nucleophiles of formula (IX) are reactedtogether as described for process f) above.

Compounds of formula (XIII) are prepared in an analogous manner to step2) in the final step of the process for preparing compounds of formula(XII) above. The necessary primary alcohol starting materials arecommercially available or are prepared by processes known in the art.

Process h)

Compounds of formula (XIV) and (XV) are reacted in an inert solvent suchas DMF in the presence of a base such as potassium carbonate.

Compounds of formula (XIV) are prepared as described in Scheme I), butomitting the first stage of the final step (i.e. no reaction with theepoxide). Compounds of formula (XV) are commercially available or areprepared by processes known in the art.

Process i)

For the compounds of formula (I) in which Z is SH, the conversion of athioacetate group in a corresponding compound is carried out asdescribed herein for the conversion of compounds of formula (IJ) into(IK).

Suitable starting materials containing a thioacetate group are preparedfrom corresponding compounds containing a leaving group such as mesylateor tosylate (prepared using standard conditions from the correspondinghydroxy compound) using thiol acetic acid as described herein for theconversion of compounds of formula (IG) into (IJ).

Examples of conversions of a compound of formula (I) into anothercompound of formula (I) are:

Conversion i) conversion of R¹ as a substituted side chain into anothersubstituted side chain, for example:

 wherein Ms is methanesulphonyl, and Nu is a nucleophile that introducesa substituent that is an optional substituent for R¹ as defined informula (I), preferably Nu is —NH₂, —NHC₁₋₄alkyl, —N(C₁₋₄alkyl)₂ or —CN(NB the hydroxyl moiety does not necessarily have to be on the terminalcarbon as depicted above);

Conversion ii): conversion of one side chain of formula (Ia) intoanother side chain of formula (Ia), for example:

EXAMPLE I

for compounds of formula (I) where Y is NH₂ (depicted below usingammonia), (1-4C)alkoxy, (1-4C)alkylthio, —NH(1-4C)alkyl,—N[(1-4C)alkyl]₂, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl,morpholino or thiomorpholino;

or:

EXAMPLE II

for compounds of formula (1) where Y is S:

EXAMPLE III

for compounds of formula (I) where Y is H:

The skilled reader will appreciate that the manipulation of the sidechain (Ia) described in Processes c), d), e), f), g) and h) andConversion ii) above and of the sidechain R¹ in Conversion i) above mayalso be performed on intermediates for example to make intermediates offormula (II), (IIA), (IIB), or (V). For example:

It will be appreciated that certain of the various ring substituents inthe compounds of the present invention may be introduced by standardaromatic substitution reactions or generated by conventional functionalgroup modifications either prior to or immediately following theprocesses mentioned above, and as such are included in the processaspect of the invention. Such reactions and modifications include, forexample, introduction of a substituent by means of an aromaticsubstitution reaction, reduction of substituents, alkylation ofsubstituents and oxidation of substituents. The reagents and reactionconditions for such procedures are well known in the chemical art.Particular examples of aromatic substitution reactions include theintroduction of a nitro group using concentrated nitric acid, theintroduction of an acyl group using, for example, an acyl halide andLewis acid (such as aluminium trichloride) under Friedel Craftsconditions; the introduction of an alkyl group using an alkyl halide andLewis acid (such as aluminium trichloride) under Friedel Craftsconditions; and the introduction of a halogeno group. Particularexamples of modifications include the reduction of a nitro group to anamino group by for example, catalytic hydrogenation with a nickelcatalyst or treatment with iron in the presence of hydrochloric acidwith heating; oxidation of alkylthio to alkylsulphinyl oralkylsulphonyl.

It will also be appreciated that in some of the reactions mentionedherein it may be necessary/desirable to protect any sensitive groups inthe compounds. The instances where protection is necessary or desirableand suitable methods for protection are known to those skilled in theart. Conventional protecting groups may be used in accordance withstandard practice (for illustration see T. W. Green, Protective Groupsin Organic Synthesis, John Wiley and Sons, 1991). Thus, if reactantsinclude groups such as amino, carboxy or hydroxy it may be desirable toprotect the group in some of the reactions mentioned herein.

A suitable protecting group for an amino or alkylamino group is, forexample, an acyl group, for example an alkanoyl group such as acetyl, analkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl ort-butoxycarbonyl group, an arylmethoxycarbonyl group, for examplebenzyloxycarbonyl, or an aroyl group, for example benzoyl. Thedeprotection conditions for the above protecting groups necessarily varywith the choice of protecting group. Thus, for example an acyl groupsuch as an alkanoyl or alkoxycarbonyl group or an aroyl group may beremoved for example, by hydrolysis with a suitable base such as analkali metal hydroxide, for example lithium or sodium hydroxide.Alternatively an acyl group such as a t-butoxycarbonyl Croup may beremoved, for example, by treatment with a suitable acid as hydrochloric,sulphuric or phosphoric acid or trifluoroacetic acid and anarylmethoxycarbonyl group such as a benzyloxycarbonyl group may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon, or by treatment with a Lewis acid for example borontris(trifluoroacetate). A suitable alternative protecting group for aprimary amino group is, for example, a phthaloyl group which may beremoved by treatment with an alkylamine, for exampledimethylaminopropylamine, or with hydrazine.

A suitable protecting group for a hydroxy group is, for example, an acylgroup, for example an alkanoyl group such as acetyl, an aroyl group, forexample benzoyl, or an arylmethyl group, for example benzyl. Thedeprotection conditions for the above protecting groups will necessarilyvary with the choice of protecting group. Thus, for example, an acylgroup such as an alkanoyl or an aroyl group may be removed, for example,by hydrolysis with a suitable base such as an alkali metal hydroxide,for example lithium or sodium hydroxide. Alternatively an arylmethylgroup such as a benzyl group may be removed, for example, byhydrogenation over a catalyst such as palladium-on-carbon.

A suitable protecting group for a carboxy group is, for example, anesterifying group, for example a methyl or an ethyl group which may beremoved, for example, by hydrolysis with a base such as sodiumhydroxide, or for example a t-butyl group which may be removed, forexample, by treatment with an acid, for example an organic acid such astrifluoroacetic acid, or for example a benzyl group which may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon.

The protecting groups may be removed at any convenient stage in thesynthesis using conventional techniques well known in the chemical art.

Many of the intermediates defined herein are novel, for example, thoseof the formula (II) and (IV) and these are provided as a further featureof the invention.

Assays

As stated hereinbefore the pyrimidine derivative defined in the presentinvention possesses anti-cell-proliferation activity such as anti-canceractivity which is believed to arise from the CDK inhibitory activity ofthe compound. These properties may be assessed, for example, using theprocedure set out below:

CDK Inhibition Assay

The following abbreviations have been used:

HEPES is N-[2-Hydroxyethyl]piperazine-N′-[2-ethanesulfonic acid]

DTT is Dithiothretiol

PMSF is Phenylmethylsulfonyl fluoride

The compounds were tested in an in vitro kinase assay in 96 well formatusing Scintillation Proximity Assay (SPA—obtained from Amersham) formeasuring incorporation of [γ-33-P]-Adenosine Triphosphate into a testsubstrate (GST-Retinoblastoma). In each well was placed the compound tobe tested (diluted in DMSO and water to correct, concentrations) and incontrol wells either p 16 as an inhibitor control or DMSO as a positivecontrol.

Approximately 0.5 μl of CDK4/Cyclin D1 partially-purified enzyme (amountdependent on enzyme activity) diluted in 25 μl incubation buffer wasadded to each well then 20 μl of GST-Rb/ATP/ATP33 mixture (containing0.54 μg GST-Rb and 0.2 μM ATP and 0.14 μCi [γ-33-P]-AdenosineTriphosphate), and the resulting mixture shaken gently, then incubatedat room temperature for 60 minutes.

To each well was then added 150 μL stop solution containing (0.8 mg/wellof Protein A-PVT SPA bead (Amersham)), 20 pM/well of Anti-GlutathioneTransferase, Rabbit IgG (obtained from Molecular Probes), 61 mM EDTA and50 mM HEPES pH 7.5 containing 0.05% sodium azide.

The plates were sealed with Topseal-S plate sealers, left for two hoursthen spun at 2500 rpm, 1124×g., for 5 minutes. The plates were read on aTopcount for 30 seconds per well.

The incubation buffer used to dilute the enzyme and substrate mixescontained 50 mM HEPES pH7.5, 10 mM MnCl₂, 1 mM DTT, 100 μM Sodiumvanadate, 100 μM NaF, 10 mM Sodium Glycerophosphate, BSA (1 mg/mlfinal).

As a control, another known inhibitor of CDK4 may be used in place ofp16.

Test Substrate

In this assay only part of the retinoblastoma (Science 1987Mar13;235(4794):1394-1399; Lee W. H., Bookstein R., Hong F., Young L.J., Shew J. Y., Lee E. Y.) was used, fused to a GST tag. PCR ofretinoblastoma amino acids 379-928 (obtained from retinoblastoma plasmidATCC pLRbRNL) was performed, and the sequence cloned into pGEX 2T fusionvector (Smith D. B. and Johnson, K. S. Gene 67, 31 (1988); whichcontained a tac promoter for inducible expression internal lac I^(q)gene for use in any E.Coli host, and a coding region for thrombincleavage—obtained from Pharmacia Biotech) which was used to amplifyamino acids 792-928. This sequence was again cloned into pGEX 2T.

The retinoblastoma 792-928 sequence so obtained was expressed in E.Coli(BL21 (DE3) pLysS cells ) using standard inducible expressiontechniques, and purified as follows.

E.coli paste was resuspended in 10 ml/g of NETN buffer (50 mM Tris pH7.5, 120 mM NaCl, 1 mM EDTA, 0.5% v/v NP-40, 1 mM PMSF, 1 ug/mlleupeptin, 1 ug/ml aprotinin and 1 ug/ml pepstatin) and sonicated for2×45 seconds per 100 ml homogenate. After centrifugation, thesupernatant was loaded onto a 10 ml glutathione Sepharose column(Pharmacia Biotech. Herts. UK), and washed with NETN buffer. Afterwashing with kinase buffer (50 mMN HEPES pH 7.5. 10 mM MgCl2, 1 mM DTT,1 mM PMSF, 1 ug/ml leupeptin, 1 ug/ml aprotinin and 1 ug/ml pepstatin)the protein was eluted with 50 mM reduced glutathione in kinase buffer.Fractions containing GST-Rb(792-927) were pooled and dialysed overnightagainst kinase buffer. The final product was analysed by Sodium DodecaSulfate (SDS) PAGE (Polyacrylamide gel) using 8-16% Tris-Glycine gels(Novex, San Diego, USA).

CDK4 and Cyclin D1

CDK4 and Cyclin D1 were cloned from RNA from NICF-7 cell line (obtainedfrom ATCC number:HTB22, breast adenocarcinoma line) as follows. The RNAwas prepared from MCF-7 cells, then reverse transcribed using oligo dTprimers. PCR was used to amplify the complete coding sequence of eachgene [CDK4 amino acids 1-303; Ref. Cell 1992 Oct 16; 71(2): 323-334;Matsushime H., Ewen M. E., Stron D. K., Kato J. Y., Hanks S. K., RousselM. F., Sherr C. J. and Cyclin D1 amino acids 1-296; Ref. Cold SpringHarb. Symp. Quant. Biol., 1991; 56:93-97; Amold A., Motokura T., BloomT., Kronenburg, Ruderman J., Juppner H., Kim H. G.].

After sequencing the PCR products were cloned using standard techniquesinto the insect expression vector pVL1393 (obtained from Invitrogen 1995catalogue number: V1392-20). The PCR products were then dually expressed[using a standard virus Baculogold co-infection technique] into theinsect SF21 cell system (Spodoptera Frugiperda cells derived fromovarian tissue of the Fall Army Worm—commercially available).

The following Example provides details of the production of CyclinD1/CDK4 in SF21 cells (in TC100+10% FBS(TCS)+0.2% Pluronic) having dualinfection MOI 3 for each virus of Cyclin D1 & CDK4.

Example Production of Cyclin D1/CDK4

SF21 cells crown in a roller bottle culture to 2.33×10⁶ cells/ml wereused to inoculate 10×500 ml roller bottles at 0.2×10E6 cells/ml. Theroller bottles were incubated on a roller rig at 28° C.

After 3 days (72 hrs.) the cells were counted, and the average from 2bottles found to be 1.86×10E6 cells/ml. (99% viable). The cultures werethen infected with the dual viruses at an MOI 3 for each virus.

10×500 ml were infected with JS303 Cyclin D1 virus titre—9×10E7 pfu/ml.JS304 CDK4 virus titre—1×10E8 pfu/ml.${{{Cyclin}\quad {D1}\quad \frac{1.86 \times 10{E6} \times 500 \times 3}{0.9 \times 10^{8}}} = {{31\quad {ml}\quad {of}\quad {virus}\quad {of}\quad {each}\quad 500\quad {{ml}.\quad {bottle}.{CDK4}}\quad \frac{1.86 \times 10{E6} \times 500 \times 3}{1 \times 10^{8}}} = {28\quad {ml}\quad {of}\quad {virus}\quad {for}\quad {each}\quad 500\quad {{ml}.\quad {bottle}.}}}}\quad$

The viruses were mixed together before addition to the cultures, and thecultures returned to the roller rig 28° C.

After 3 days (72 hrs.) post infection the 5 Litres of culture washarvested. The total cell count at harvest was 1.58×10E6 cells/ml.(99%viable). The cells were spun out at 2500 rpm, 30 mins., 4° C. in HeraeusOmnifuge 2.0 RS in 250 mls. lots. The supernatant was discarded.

20 pellets of ˜4×10E8 cells/pellet were snap frozen in LN₂ and stored at−80° C. in CCRF cold room. The SF21 cells were then hypotonically lysedby resuspending in lysis buffer (50 mM HEPES pH 7.5, 10 mM magnesiumchloride, 1 mM DTT, 10 mM glycerophosphate, 0.1 mM PMSF, 0.1 mM sodiumfluoride, 0.1 mM sodium orthovanadate, 5 ug/ml aprotinin, 5 ug/mlleupeptin and 20% w/v sucrose), and adding ice cold deionised water.After centrifugation, the supernatant was loaded onto a Poros HQ/M1.4/100 anion exchange column (PE Biosystems, Hertford, UK). CDK4 andCyclin D1 were coeluted with 375 mM NaCl in lysis buffer, and theirpresence checked by western blot, using suitable anti-CDK4 andanti-Cyclin D1 antibodies (obtained from Santa Cruz Biotechnology,California, US).

p16 Control (Nature 366.:704-707; 1993: Serrano M. Hannon G J. Beach D)

p16 (the natural inhibitor of CDK4/Cyclin D1) was amplified from HeLacDNA (Hela cells obtained from ATCC CCL2, human epitheloid carcinomafrom cervix; Cancer Res. 12: 264, 1952), cloned into pTB 375 NBSE whichhad a 5′ His tag, and transformed using standard techniques into BL21(DE3) pLysS cells (obtained from Promega; Ref. Studier F. W. and MtoffatB. A., J. Mol. Biol., 189, 113, 1986). A 1 liter culture was grown tothe appropriate OD then induced with IPTG to express p16 overnight. Thecells were then lysed by sonication in 50 mM sodium phoshate, 0.5 Msodium chloride, PMSF, 0.5 μg/mL leupeptin and 0.5 μg/mL aprotinin. Themixture was spun doen, the supernatant added to nickel chelate beads andmixed for 1½ hours. The beads were washed in sodium phosphate, NaCl pH6.0 and p16 product eluted in sodium phosphate, NaCl pH 7.4 with 200 mMimidazole.

The pTB NBSE was constructed from pTB 375 NBPE as follows:

pTB375

The background vector used for generation of pTB 375 was pZEN0042 (seeUK patent 2253852) and contained the tetA/tetR inducble tetracyclineresistance sequence from plasmid RP4 and the cer stability sequence fromplasmid pKS492 in a pAT153 derived background. pTB375 was generated bythe addition of an expression cassette consisting of the T7 gene 10promoter, multiple cloning site and T7 gene 10 termination sequence. Inaddition, a terminator sequence designed to reduce transcriptionalreadthrough from the background vector was included upstream of theexpression cassette.

pTB 375 NBPE

The unique EcoRI restriction site present in pTB 375 was removed. A newmultiple cloning site containing the recognition sequences for therestriction enzymes NdeI, BamHI, PstI and EcoRI was introduced into pTB375 between the NdeI and BamHI sites destroying the original BamHI sitepresent in pTB 375.

pTB 375 NBSE

A new multiple cloning site containing the recognition sequences for therestriction enzvmes NdeI, BamHI, SmaI and EcoRI was introduced into pTB375 NBPE between the NdeI and EcoRI sites. The oligonucleotidecontaining these restriction sites also contained 6 histidine codonslocated between the NdeI and BamHI sites in the same reading frame asthe inititiator codon (ATG) present within the Ndel site.

By analogy to the above, assays designed to assess inhibition of CDK2and CDK6 may be constructed. CDK2 (EMBL Accession No. X62071) may beused together with Cyclin A or Cvclin E (see EMBL Accession No. M73812),and further details for such assays are contained in PCT InternationalPublication No. WO99/21845, the relevant Biochemical & BiologicalEvaluation sections of which are hereby incorporated by reference.

If using CDK-2 with Cyclin E partial co-purification may be achieved asfollows:

Sf21 cells are resuspended in lysis buffer (50 mM Tris pH 8.2, 10 mMMgCl₂, 1 mM DTT, 10 mM glycerophosphate, 0.1 mM sodium orthovanadate,0.1 mM NaF, 1 mM PMSF, 1 ug/ml leupeptin and 1 ug/ml aprotinin) andhomogenised for 2 minutes in a 10 ml Dounce homgeniser. Aftercentrifugation, the supernatant is loaded onto a Poros HQ/M 1.4/100anion exchange column (PE Biosystems, Hertford, UK). CDK-2 and Cyclin Eare coeluted at the beginning of a 0-1M NaCl gradient (run in lysisbuffer minus protease inhibitors) over 20 column volumes. Co-elution ischecked by western blot using both anti-CDK-2 and anti-Cyclin Eantibodies (Santa Cruz Biotechnology, California, US).

Although the pharmacological properties of the compounds of the formula(I) vary with structural change, in general activity possessed bycompounds of the formula (I) in the above assays may be demonstrated atIC₅₀ concentrations or doses in the range 250 μM to 1 nM.

When tested in the above in-vitro assay the CDK4 inhibitory activity ofExample 1 was measured as IC₅₀=0.11 μM and that of Example 2 asIC₅₀=0.07 μM.

The in-vivo activity of the compounds of the present invention may beassessed by standard techniques, for example by measuring inhibition ofcell growth and assessing cytotoxicity.

Inhibition of cell growth may be measured by staining cells withSulforhodamine B (SRB), a fluorescent dye that stains proteins andtherefore gives an estimation of amount of protein (i.e. cells) in awell (see Boyd, M. R.(1989) Status of the NCI preclinical antitumourdrug discovery screen. Prin. Prac Oncol 10:1-12). Thus, the followingdetails are provided of measuring inhibition of cell growth:

Cells were plated in appropriate medium in a volume of 100 μl in 96 wellplates; media was Dulbecco's Modified Eagle media for MCF-7, SK-UT-1Band SK-UT-1. The cells were allowed to attach ovemight, then inhibitorcompounds were added at various concentrations in a maximumconcentration of 1% DNISO (v/v). A control plate was assayed to give avalue for cells before dosing. Cells were incubated at 37° C., (5% CO2)for three days.

At the end of three days TCA was added to the plates to a finalconcentration of 16% (v/v). Plates were then incubated at 4° C. for 1hour, the supernatant removed and the plates washed in tap water. Afterdrying, 100 μl SRB dye (0.4% SRB in 1% acetic acid) was added for 30minutes at 37° C. Excess SRB was removed and the plates washed in 1%acetic acid. The SRB bound to protein was solubilised in 10 mM TrispH7.5 and shaken for 30 minutes at room temperature. The ODs were readat 540 nm, and the concentration of inhibitor causing 50% inhibition ofgrowth was determined from a semi-log plot of inhibitor concentrationversus absorbance. The concentration of compound that reduced theoptical density to below that obtained when the cells were plated at thestart of the experiment gave the value for toxicity.

Typical IC₅₀ values for compounds of the invention when tested in theSRB assay are in the range 1 mM to 1 nM.

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a pyrimidine derivative ofthe formula (I), or a pharmaceutically-acceptable salt or in-vivohydrolysable ester thereof, as defined hereinbefore in association witha pharmaceutically-acceptable diluent or carrier.

The composition may be in a form suitable for oral administration, forexample as a tablet or capsule, for parenteral injection (includingintraveous, subcutaneous, intramuscular, intravascular or infusion) as asterile solution, suspension or emulsion, for topical administration asan ointment or cream or for rectal administration as a suppository.

In general the above compositions may be prepared in a conventionalmanner using conventional excipients.

The pyrimidine will normally be administered to a warm-blooded animal ata unit dose within the range 5-5000 mg per square meter body area of theanimal, i.e. approximately 0.1-100 mg/kg, and this normally provides atherapeutically-effective dose. A unit dose form such as a tablet orcapsule will usually contain, for example 1-250 mg of active ingredient.Preferably a daily dose in the range of 1-50 mg/kg is employed. Howeverthe daily dose will necessarily be varied depending upon the hosttreated, the particular route of administration, and the severity of theillness being treated. Accordingly the optimum dosage may be determinedby the practitioner who is treating any particular patient.

According to a mother aspect of the present invention there is provideda pyrimidine derivative of the formula (I), or apharmaceutically-acceptable salt or in-vivo hydrolysable ester thereof,as defined hereinbefore for use in a method of treatment of the human oranimal body by therapy.

We have found that the pyrimidine derivatives defined in the presentinvention, or a pharmaceutically-acceptable salt or in-vivo hydrolysableester thereof, are effective cell cycle inhibitors (anti-cellproliferation agents), which property (without being bound by theory) isbelieved to arise from their (G1-S phase) CDK inhibitory properties.Accordingly the compounds of the present invention are expected to beuseful in the treatment of diseases or medical conditions mediated aloneor in part by CDK enzymes, i.e. the compounds may be used to produce aCDK inhibitory effect in a warm-blooded animal in need of suchtreatment. Thus the compounds of the present invention provide a methodfor treating the proliferation of malignant cells characterised byinhibition of CDK enzymes, i.e. the compounds may be used to produce ananti-proliferative effect mediated alone or in part by the inhibition ofCDKs. Such a pyrimidine derivative of the invention is expected topossess a wide range of anti-cancer properties as CDKs have beenimplicated in many common human cancers such as leukaemia and breast,lung, colon, rectal, stomach, prostate, bladder, pancreas and ovariancancer. Thus it is expected that a pyrimidine derivative of theinvention will possess anti-cancer activity against these cancers. It isin addition expected that a pyrimidine derivative of the presentinvention will possess activity against a range of leukaemias, lymphoidmalignancies and solid tumours such as carcinomas and sarcomas intissues such as the liver, kidney, prostate and pancreas. In particularsuch compounds of the invention are expected to slow advantageously thegrowth of primary and recurrent solid tumours of, for example, thecolon, breast, prostate, lungs and skin. More particularly suchcompounds of the invention, or a pharmaceutically-acceptable salt orin-vivo hydrolysable ester thereof, are expected to inhibit the growthof those primary and recurrent solid tumours which are associated withCDKs, especially those tumours which are significantly dependent on CDKfor their growth and spread, including for example, certain tumours ofthe colon, breast, prostate lung, vulva and skin.

It is further expected that a pyrimidine derivative of the presentinvention will possess activity against other cell-proliferationdiseases in a wide range of other disease states including leukemias,fibroproliferative and differentiative disorders, psoriasis, rheumatoidarthritis, Kaposi's sarcoma, haemangioma, acute and chronicnephropathies, atheroma, atherosclerosis, arterial restenosis,autoimmune diseases, acute and chronic inflammation, bone diseases andocular diseases with retinal vessel proliferation.

Thus according to this aspect of the invention there is provided apyrimidine derivative of the formula (I), or apharmaceutically-acceptable salt or in-vivo hydrolysable ester thereof,as defined hereinbefore for use as a medicament; and the use of apyrimidine derivative of the formula (I), or apharmaceutically-acceptable salt or in-vivo hydrolysable ester thereof,as defined hereinbefore in the manufacture of a medicament for use inthe production of an anti-cancer, cell cycle inhibitory(anti-cell-proliferation) effect in a warm-blooded animal such as man.Particularly, a cell cycle inhibitory effect is produced at the G1-Sphase by inhibition of CDK2, CDK4 and/or CDK6, especially CDK4 and CDK6.

According to a further feature of this aspect of the invention there isprovided a method for producing an anti-cancer, cell cycle inhibitory(anti-cell-proliferation) effect in a warm-blooded animal, such as man,in need of such treatment which comprises administering to said animalan effective amount of a pyrimidine derivative as defined immediatelyabove. Particularly, an inhibitory effect is produced at the G1-S phaseby inhibition of CDK2, CDK4 and/or CDK6, especially CDK4 and CDK6.

As stated above the size of the dose required for the therapeutic orprophylactic treatment of a particular cell-proliferation disease willnecessarily be varied depending on the host treated, the route ofadministration and the severity of the illness being treated. A unitdose in the range, for example, 1-100 mg/kg, preferably 1-50 mg/kg isenvisaged.

The CDK inhibitory activity defined hereinbefore may be applied as asole therapy or may involve, in addition to a compound of the invention,one or more other substances and/or treatments. Such conjoint treatmentmay be achieved by way of the simultaneous, sequential or separateadministration of the individual components of the treatment. In thefield of medical oncology it is normal practice to use a combination ofdifferent forms of treatment to treat each patient with cancer. Inmedical oncology the other component(s) of such conjoint treatment inaddition to the cell cycle inhibitory treatment defined hereinbefore maybe: surgery, radiotherapy or chemotherapy. Such chemotherapy may coverthree main categories of therapeutic agent:

(i) other cell cycle inhibitory agents that work by the same ordifferent mechanisms from those defined hereinbefore;

(ii) cytostatic agents such as antioestrogens (for exampletamoxifen,toremifene, raloxifene, droloxifene, lodoxyfene), progestogens(for example megestrol acetate), aromatase inhibitors (for exampleanastrozole, letrazole, vorazole, exemestane), antiprogestogens,antiandrogens (for example flutamide, nilutamide, bicalutarnide,cyproterone acetate), LHRH agonists and antagonists (for exampleaoserelin acetate, luprolide), inhibitors of testosterone5α-dihydroreductase (for example finasteride), anti-invasion agents (forexample metalloproteinase inhibitors like marimastat and inhibitors ofurokinase plasminogen activator receptor function) and inhibitors ofgrowth factor function, (such growth factors include for exampleplatelet derived growth factor and hepatocyte growth factor suchinhibitors include growth factor antibodies, growth factor receptorantibodies, tyrosine kinase inhibitors and serine/threonine kinaseinhibitors); and

(iii) antiproliferative/antineoplastic drugs and combinations thereof,as used in medical oncology, such as antimetabolites (for exampleantifolates like methotrexate, fluoropyrimidines like 5-fluorouracil,purine and adenosine analogues, cytosine arabinoside); antitumourantibiotics (for example anthracyclines like doxorubicin, daunomycin,epirubicin and idarubicin, mitomycin-C, dactinomycin, mithramycin);platinum derivatives (for example cisplatin, carboplatin); alkylatingagents (for example nitrogen mustard, melphalan, chlorambucil,busulphan, cyclophosphamide, ifosfamide, nitrosoureas, thiotepa);antimitotic agents (for example vinca alkaloids like vincrisitine andtaxoids like taxol, taxotere); topoisomerase inhibitors (for exampleepipodophyllotoxins like etoposide and teniposide, amsacrine,topotecan). According to this aspect of the invention there is provideda pharmaceutical product comprising a pyrimidine derivative of theformula (I) as defined hereinbefore and an additional anti-tumoursubstance as defined hereinbefore for the conjoint treatment of cancer.An anti-emetic may also be usefully administered, for example when usingsuch conjoint treatment as described above.

In addition to their use in therapeutic medicine, the compounds offormula (I) and their pharmaceutically acceptable salts are also usefulas pharmacological tools in the development and standardisation of invitro and in vivo rest svstems for the evaluation of the effects ofinhibitors of cell cycle activity in laboratory animals such as cats,dogs, rabbits, monkeys, rats and mice, as part of the search for newtherapeutic agents.

In the above other, pharmaceutical composition, process, method, use andmedicament manufacture features, the alternative and preferredembodiments of the compounds of the invention described herein alsoapply.

EXAMPLES

The invention will now be illustrated in the following non-limitingExamples, in which standard techniques known to the skilled chemist andtechniques analogous to those described in these Examples may be usedwhere appropriate, and in which, unless otherwise stated:

(i) evaporations were carried out by rotary evaporation in vacuo andwork-up procedures were carried out after removal of residual solidssuch as drying agents by filtration;

(ii) operations were carried out at ambient temperature, typically inthe range 18-25° C. and in air unless stated, or unless the skilledperson would otherwise operate under an atmosphere of an inert gas suchas argon;

(iii) column chromatography (by the flash procedure) and medium pressureliquid chromatography (MPLC), for example using an Anachem Sympur MPLC,were performed on Merck Kieselgel silica (Art. 9385) or Merck LichroprepRP-18 (Art. 9303) reversed-phase silica obtained from E. Merck,Darmstadt, Germany; where a Mega Bond Elut column is referred to, thismeans a column containing 10 g or 20 g of silica of 40 micron particlesize, the silica being contained in a 60 ml disposable syringe andsupported by a porous disc, obtained from Varian, Harbor City, Calif.,USA under the name “Mega Bond Elut SI”; “Mega Bond Elut” is a trademark;

(iv) yields are given for illustration only and are not necessarily themaximum attainable;

(v) the structures of the end products of the formula (I) were generallyconfirmed by nuclear (generally proton) magnetic resonance (NMR) andmass spectral techniques; proton magnetic resonance chemical shiftvalues were measured in deuterated DNISO (unless otherwise stated); atambient temperature unless marked 373K; on the delta scale (ppmdownfield from tetramethylsilane); using a Varian Gemini 2000spectrometer operating at a field strength of 300 MHz or a Bruker DPX400spectrometer operating at a field strength of 400 MHz; and peakmultilicities are shown as follows: s, singlet; d, doublet; t, triplet;m, multiplet; br, broad; mass spectrometry (MS) was performed byelectrospray on a VG platform;,

(vi) intermediates were not generally fully characterised and purity wasassessed by thin layer chromatography (TLC), high performance liquidchromatography (HPLC), infra-red (IR), MS or NMR analysis;

(vii) it is to be understood that in this Examples section certainsymbols, such as R₁ and R₂, have been used to describe certain Examplesin Tables, and that the use of such symbols should be read in contextwith the Examples to which they refer;

(viii) certain geometric isomers (such as in Examples 11 & 17) may existas E- and Z-isomers; it is to be understood that where one isomer, or noparticular isomer, is shown this refers to a mixture of both isomers;

(ix) the following abbreviations may be used hereinbefore orhereinafter:

DMF N,N-dimethylformamide; CDCl₃ deuterated chloroform; MeOH-δ4deuterated methanol; EA elemental analysis; NMP1-methyl-2-pyrrolidinone; DEAD diethyl azodicarboxylate; DTADditertbutyl azodicarboxylate; EtOH ethanol; DIPEA diisopropylethylamine;DCM dichloromethane; TFA trifluoroacetic acid; EtOAc ethyl acetate; andDMSO dimethylsulphoxide.

Example 14-{4-[3-(N,N-Dimethyl)amino-2-hydroxyproroxy]anilino}-6-(N-cyanomethyl-2-bromo-4-methylanilino)pyrimidine

To a solution of4-(4-hydroxyanilino)-6-(N-cyanomethyl-2-bromo-4-methylanilino)pyrimidine(Reference Example 1, 560 mg) in DMSO (2 ml) was added potassiumcarbonate (565 mg) and epibromohydrin (280 mg) and the reaction mixturewas stirred at ambient temperature for 24 hours. Dimethylamine (2M inMeOH, 2.72 ml) was added and the reaction was stirred for a further 5hours. The mixture was poured into water (50 ml) and extracted withEtOAc. The organic extract was dried (MgSO₄) and evaporated. The residuewas purified by column chromatography eluting with DCM:MeOH:concentrated ammonia; 87:12:1 to give the title compound (503 mg, 72%)as a solid. NMR: 2.16 (6H, s), 2.20-2.38 (5H, m), 3.70-3.92 (3H, m),4.56-4.70 (1H, brd), 4.73 (1H, d), 4.97-514 (1H, brd), 5.29 (1H, s),6.80 (2H, d), 7.33-7.41 (4H, m), 7.70 (1H, s), 8.31 (1H, s), 8.94 (1H,s); m/z 511 (MH⁺).

Example 24-{4-[3-(N,N-Dimethyl)amino-2-hydroxylropoxy]anilino}-6-(N-cyanomethyl-2-chloro-5-methylanilino)pyrimidine

To a solution of4-(4-hydroxyanilino)-6-(2-chloro-5-methylanilino)pyrimidine (ReferenceExample 6, 1.03 g) in DMSO (6 ml) was added potassium carbonate (870 mg)and epibromohydrin (474 mg) and the reaction was stirred for 18 hours.Potassium carbonate (1.3 g) and bromoacetonitrile (754 mg) were addedand the mixture was stirred for a futher 4 hours. Dimethylamine (2Msolution in MeOH, 6ml) was added and the reaction was stirred for anadditional 4 hours. The mixture was concentrated and the residuepartitioned between EtOAc and saturated aqueous sodium chloridesolution. The organic extract was separated, dried (MgSO₄) andevaporated. The residue was purified by column chromatography elutingwith DCM:MeOH:concentrated ammonia; 90:9:1 to give the title compound(230 mg, 16%) as an oil. NMR: 2.04 (6H, s), 2.08-2.15 (5H, m), 3.61-3.80(3H, m), 4.00 (1H, d), 5.20 (1H, s), 6.69 (2H, d), 7.15-7.28 (3H, m),7.46 (1H, d), 8.19 (1H, s), 8.84 (1H, s); m/z 467 (MH⁺).

Preparation of Starting Materials for Examples 1 and 2

The starting materials for the Examples above are either commerciallyavailable or are readily prepared by standard methods from knownmaterials. For example the following reactions are illustrations but notlimitations of the preparation of some of the starting materials used inthe above reactions.

Method A Reference Example 14-(4-Hydroxyanilino)-6-(N-cyanomethyl-2-bromo-4-methylanilino)pyrimidine

To a solution of4-(4-tertbutyldimethylsilyloxyanilino)-6-(N-cyanomethyl-2-bromo-4-methylanilino)pyrimidine(Reference Example 2, 890 mg) in tetrahydrofuran (1 ml) was addedN,N,N,N-tetraburylammonium fluoride (1M solution in tetrahydrofuran, 2ml). The reaction mixture was stirred at ambient temperature for 30minutes. The solvent was evaporated and the residue partitioned betweenEtOAc and water. The organic layer was separated and dried (MgSO₄),evaporated and purified by column chromatography eluting withDCM:MeOH:concentrated ammonia; 95:4:1 to give the title compound (510mg, 73%) as a solid. M/z 410 (MH⁺).

Method B Reference Example 24-(4-Tertbutyldimethylsilyloxyanilino)-6-(N-cyanomethyl-2-bromo-4-methylanilino)pyrimidine

To a solution of4-(4-tertbutyldimethylsilyloxyanilino)-6-(2-bromo-4-methylanilino)pyrimidine(Reference Example 3, 396 mg) in tetrahydrofuiran (1 ml) under nitrogenatmosphere was added portion wise sodium hydride (60% dispersion inmineral oil, 58 mg). The solution was stirred for 30 minutes.Bromoacetonitrile (131 mg) was added and the reaction stirred for afurther 1 hour. The solvent was evaporated and the residue purified bycolumn chromatography eluting with DCM:MeOH:concentrated ammonia;97.8:2:0.2 to give the title compound (158 mg, 37%) as a solid. M/z 524(MH⁺).

Method C Reference Example 34-(4-Tertbutyldimethylsilyoxyanilino)-6-(2-bromo-4-methylanilino)pyrimidine

To a solution of4-(4-hydroxyanilino)-6-(2-bromo-4-methylanilino)pyrimidine (ReferenceExample 4, 4 g) in chloroform (120 ml) was added imidazole (2.2 g) andtert-butylchlorodimethylsilane (2.4 g) and the reaction mixture wasstirred for 12 hours. A saturated aqueous solution of sodiumhydrogencarbonate (50 ml) was added and the mixture stirred for afurther 30 minutes. The organic extract was dried (MgSO₄) and evaporatedto dryness. The residue was purified by column chromatography elutingwith DCM:MeOH:concentrated ammonia; 98.8:1:0.2 to give the titlecompound (4.3 g, 83%) as a white solid. M/z 485 (MH⁺).

Method D Reference Example 44-(4-Hydroxyanilino)-6-(2-bromo-4-methylanilino)pyrimidine

To a solution of 4-(4-hydroxyanilino)-6-chloropyrimidine (ReferenceExample 5, 5 g) was added 2-bromo-4-methylaniline (7.5 ml) and thereaction mixture was heated at 195° C. for 24 hours. The residue wasabsorbed onto silica and purified by column chromatography eluting withDCM:MeOH (19:1) to give the title compound (336 mg, 4%). NMR: 2.28 (3H,s), 5.72 (1H, s), 6.68 (2H, d), 7.17 (3H, m), 7.39 (1H, d), 7.48 (1H,s), 8.05 (1H, s), 8.38 (1H, s), 8.65 (1H, s), 9.08 (1H, s); m/z 371(MH⁺).

Method E Reference Example 5 4-(4-Hydroxyanilino)-6-chloropyrimidine

To a solution of 4,6-dichloropyrimidine (24.8 g), ethanol (250 ml) andtriethylamine (51 ml) was added 4-aminophenol (18.2 g) and the solutionwas heated at reflux for 6 hours. After cooling the precipitate wascollected, washed with DCM (100 ml) and recrystallized in acetonitrileto give the title compound (25.6 g, 69%) as crystals. NMR: 6.59 (1H, s),6.73 (2H, d), 7.28 (2H, d), 8.33 (1H, s), 9.28 (1H, s), 9.52 (1H, s);m/z 222 (NH⁺).

Method F Reference Example 64-(4-Hydroxyanilino)-6-(2-chloro-5-methylanilino)pyrimidine

The title compound was prepared in a similar manner to that of ReferenceExample 4 from 4-(4-hydroxyanilino)-6-chloropyrimidine (ReferenceExample 5) by reaction with 2-chloro-5-methylaniline in butan-1-ol inthe presence of catalytic concentrated hydrochloric acid. The mixturewas heated at reflux for 18 hours, concentrated and the residue purifiedby column chromatography eluting with DCMN:MeOH: concentrated ammonia(94:5:1). Yield 84%. NMR: 2.26 (3H, s), 5.85 (1H, s), 6.68 (2H, d), 6.93(1H, d), 7.19 (2H, d), 7.32 (1H, d), 7.46 (1H, s), 8.09 (1H, s), 8.44(1H, s), 8.69 (1H, s), 9.11 (1H, s); m/z 327 (MH⁺).

Example 34-{4-[3-(N,N-Dimethyl)amino-2-hydroxypropoxy]anilino}-6-[N-(2-cyanoethyl)-2,5-dichloroanilino]pyrimidine

To a solution of4-{4-[2,3-epoxypropoxy]anilino}-6-[N-(2-cyanoethyl)-2,5-dichloroanilino]pyrimidine(Reference Example 7, 396 mg) in DMF (2 ml) was added dimethylamine (2Min MeOH, 3.5 ml) and the reaction stirred for 6 hours. The mixture waspoured into water and extracted with EtOAc. The organic extract wasdried (MgSO₄) and evaporated. The residue was purified by columnchromatography eluting with DCM:MeOH:concentrated ammonia; 91:8:1 togive the product (366 mg, 84%) as a colourless oil. NMR: 2.15 (6H, s),2.20-2.42 (2H, m), 2.84 (2H, m), 3.72-4.22 (5H, m), 4.77 (1H, d), 5.27(1H, s), 6.81 (2H, d), 7.37 (2H, d), 7.56 (1H, dd), 7.76 (2H, m), 8.22(1H, s), 8.88 (1H, s); m/z 501 (MH⁺).

Examples 4-7

The following compounds were prepared by an analogous method to thatdescribed in Example 3 using the appropriate N-alkylated epoxidestarting material of Formula G (prepared by the procedure of Method Gand the corresponding Reference Examples 7 and 8—see below).

Formula A

Ex M/z No R₁ R₂ NMR (MH⁺) 4† 2,5-diCl —CH₂C≡CH 2.19(6H, s), 4862.20-2.42(2H, m), 3.13-3.22(1H, m), 3.72-3.95 (3H, m), 4.50-4.80(3H, m),5.41(1H, s), 6.81(2H, d), 7.39(2H, d), 7.50-7.75(3H, m), 8.22(1H, s),8.94(1H, s) 5 2,5-diCl —CH₂Ph 2.14-2.39(8H, m), 538 3.73-3.94(3H, m),4.72(1H, m), 5.07(2H, brs), 5.36(1H, s), 6.79(2H, d), 7.17-7.46(9H, m),7.62(1H, d), 8.21(1H, s), 8.85(1H, s) 6† 2,5-diCl —CH₂CN 2.19(6H, s),487 2.21-2.42(2H, m), 3.73-3.92(3H, m), 4.77(1H, s), 4.91(2H, s),5.39(1H, s), 6.81(2H, d), 7.39(2H, d), 7.60(1H, dd), 7.70(1H, m),7.78(1H, d), 8.32(1H, s), 9.00(1H, s) 7†,* 2,4-diF —CH₂CH₂F 2.18(6H, s),462 2.20-2.40(2H, m), 3.71-3.90(3H, m), 4.07(1H, t), 4.18(1H, t),4.53(1H, t), 4.67(1H, t), 4.74(1H, m), 5.40(1H, s), 6.80(2H, d),7.21(1H, t), 7.38(2H, d), 7.40-7.59(2H, m), 8.19(1H, s), 8.80(1H, s) †NoDMF was used. *Starting Material is Reference Example 8

Example 84-{4-[3-(N,N-Dimethyl)amino-2-hydroxypropoxy]anilino}-6-[N-(4-methoxybenzyl)-2,5-dichloroanilino]pyrimidine

To a solution of4-{4-[2,3-epoxypropoxy]anilino}-6-(2,5-dichloroanilino)pyrimidine(Reference Example 9; 316 ma) in DMF (3 ml) was added potassiumtert-butoxide (1M solution in tetrahydrofuran. 0.86 ml) at −35° C. andthe solution stirred for 30 minutes. 4-Methoxybenzyl bromide (0.32 ml)was then added and the solution allowed to warm to ambient temperatureover 2.5 hours. After stirring for 1 hour at ambient temperature,dimethylamine (2M in MeOH, 2 ml) was added and the reaction stirred fora further 18 hours. The solution was then poured into water andextracted with EtOAc. The organic extract was dried (MgSO₄) andevaporated. The residue was purified by column chromatography elutingwith DCM:MeOH:concentrated ammonia; 91:8:1 to give the title compound(220 mg, 49%) as a colourless oil. NMR: 2.19 (6H, s), 2.21-2.40 (2H, m),3.68-3.92 (6H, m), 4.76 (1H, m), 4.95 (2H, brs), 5.38 (1H, s), 6.81 (4H,m), 7.19 (2H, m), 7.35 (3H, m), 7.42 (1H, dd), 7.61 (1H; d), 8.21 (1H,s), 8.83 (1H, s); m/z 568 (MH⁺).

Examples 9-11

The following compounds of Formula A were prepared by the method ofExample 8 using the appropriate un-N-alkylated epoxides of Formula H(prepared by the procedure of Method H and the corresponding ReferenceExample 9—see below) and the appropriate bromo-substituted alkylatingagent (apart from Example 9 in which1-(3-bromopropyl)-2,2,5,5-tetramethyl-1-aza-2,5-disilacylopentane (97%)was used as the alkylating agent, and which hydrolysed under thereaction conditions to give the R₂=—CH₂CH₂CH₂NH₂ product).

Ex M/z No R₁ R₂ NMR (MH⁺⁾  9 2,5- —CH₂CH₂CH₂NH₂ 1.40-1.70 (4H, m),2.19-2.42 505 diCl (8H, m), 2.56 (2H, t), 3.71- 3.98 (5H, m), 4.75 (1H,s), 5.38 (1H, s), 6.81 (2H, d), 7.39 (2H, d), 7.49 (1H, dd), 7.60 (1H,m), 7.67 (1H, d), 8.18 (1H, s), 8.80 (1H,s) 10 2,5- —CH₂CH₂CH₂CF₃ 1.78(2H, m), 2.19 (6H, s) 558 diCl 2.21-2.44 (4H, m), 3.71-3.96 (5H, m),4.76 (1H, m), 5.24 (1H, s), 6.80 (2H, d), 7.38 (2H, d), 7.52 (1H, dd),7.71 (2H, m), 8.20 (1H, s), 8.80 (1H, s) 11 2,5- —CH₂CH═CHBr* 2.20-2.44(8H, m), 3.71-3.96 566 diCl (3H, m), 4.30-4.68 (2H, m), 4.77 (1H, s),5.37 (1H, s), 6.28-6.60 (2H, m), 6.83 (2H, d), 7.39 (2H, d), 7.52 (1H,m), 7.71 (2H, m), 8.21 (1H, s), 8.87 (1H, s) *Mixture of E- and Z-isomers

Example 124-{4-[3-(N,N-Dimethyl)amino-2-hydroxyoropoxy]anilino}-6-(N-cyanomethyl-2,4-difluoroanilino)pyrimidine

The title compound was made by the procedure of Example 1 (using4-(4-hydroxyanilino)-6-(N-cyanomethyl-2,4-difluoroanilino)pyrimidine asa starting material (prepared by an analogous procedure to ReferenceExamples 1-4 and using the appropriate aniline). Yield: 131 mg, 46%.NMR: 2.18 (6H, s), 2.20-2.40 (2H, m), 3.73-3.92 (3H, m), 4.74 (1H, d),5.49 (1H, s), 6.83 (1H, d), 7.28 (1H, m), 7.37 (2H, d), 7.49-7.64 (2H,m), 8.32 (1H, s), 8.98 (1H, m): m/z 455 (MH⁺).

Preparation of Starting Materials for Examples 3-12

Method G

The starting materials for the above Examples are readily prepared andisolated by standard methods. The following reactions (ReferenceExamples 7 and 8) are illustrations of the preparation of theN-alkylated epoxide starting materials of Formula G used in the abovereactions.

Reference Example 74-{4-[2,3-Epoxypropoxy]anilino}-6-[N-(2-cyanoethyl)-2,5-dichloroanilino]pyrimidine

To a solution of4-{4-[2,3-epoxypropoxy]anilino}-6-(2,5-dichloroanilino)pyrimidine(Reference Example 9, 1.4 g) in DMSO (3.75 ml) was added K₂CO₃ (1.1 g)and 3-bromopropionitrile (0.66 ml) and the reaction stirred for 20hours. The mixture was poured into water and extracted with EtOAc. Theorganic extract was dried (MgSO₄) and evaporated. The residue waspurified by column chromatography eluting with DCM:MeOH; 99:1 to givethe product (436 mg, 26%) as a colourless oil. NMR: 2.66 (1H, t),2.78-2.92 (3H, m), 3.76 (1H, dd), 3.82-4.36 (3H, m), 5.28 (1H, s), 6.82(2H, d), 7.38 (2H, d), 7.57 (1H, dd), 7.72 (1H, m), 8.25 (1H, s), 8.89(1H, s); m/z 456(MH⁺).

Reference ExamDle 84-[4-(2,3-Epoxypropoxy)anilino]-6-[N-(2-fluoroethyl)-2,4-difluoroanilino]pyrimidine

To a solution of4-[4-(2,3-epoxypropoxy)anilino]-6-(2,4-difluoroanilino)pyrimidine(prepared by an analogous procedure to Reference Examples 9 and usingthe appropriate aniline) (1.4 g) in DMF (11 ml) at 0° C. was addedsodium tert-butoxide (580 mg) and the mixture stirred for 10 minutes. Toa portion of this solution (2.2 ml) was added 1-bromo-2-fluoroethane(0.11 ml) and the reaction stirred for 1 hour. The solution was thenpoured into water and extracted with EtOAc. The organic extract wasdried (MgSO₄) and evaporated. The residue was purified by columnchromatography eluting with DCM:MeOH; 125:2 to give the product (237 mg,75%) as a colourless oil. NMR: 2.65 (2H, m), 2.81 (2H, m), 3.79 (1H,dd), 4.01-4.18 (2H, m), 4.51 (2H, t), 4.67 (2H, t), 5.40 (1H, s), 6.82(2H, d), 7.21 (1H, m), 7.30-7.59 (4H, m), 8.20 (1H, s), 8.84 (1H, s).

Method H

Un-N-alkylated epoxides of Formula H may be obtained by reaction of4,6-dichloropyrimidine:

a) with 4-hydroxyaniline (see Reference Example 5), then

b) reaction with the relevant (R₁ substituted)aniline (see ReferenceExample 4), then

c) formation of the epoxide with epibromhydrin (see Reference Example9).

Alternatively, steps a) and b) may be reversed.

The starting materials for the above Examples are readily prepared andisolated by standard methods. The following reaction (Reference Example9) illustrates the preparation of the un-N-alkylated epoxide startingmaterials of Formula H used in the above reactions.

Reference Example 94-{4-[2,3-Epoxyproxy]anilino}-6-(2,5-dichloroanilino)pyrimidine

To a solution of 4-(4-hydroxyanilino)-6-(2,5-dichloroanilino)pyrimidine(prepared by analogy to Reference Example 6 using the appropriateaniline; 2.83 g) and powdered K₂CO₃ (2.25 g) in DMSO was addedepibromohydrin (0.98 ml) and the reaction stirred for 21 hours. Thesolution was poured into water and extracted with EtOAc. The organicextract was washed with brine, dried (MgSO₄) and evaporated over silica.The residue was purified by column chromatography eluting withDCM:MeOOH; 50:1 to give the title compound (2.76 g, 84%) as a whitesolid. NMR: 2.69 (1H, dd), 2.83 (1H, dd), 3.31 (1H, m), 3.80 (1H, dd),4.28 (1H, dd), 6.15 (1H, s), 6.92 (2H, d), 7.13 (1H, dd), 7.38 (2H, d),7.48 (1H, d), 8.00 (1H, m), 8.20 (1H, s), 8.71 (1H, s), 8.99 (1H, s);m/z 403 (MH⁺).

Examples 13-14

The following compounds of Formula A were prepared by an analogousmethod to that described in Example 1 using the appropriate 4-hydroxycompounds (see Reference Examples 10 and 11 below).

Ex M/z No R₁ R₂ NMR (300 MHz) (MH⁺⁾ 13 2,4- CH₃ 2.14 (s, 6H), 2.25 (m,1H), 2.36 430.4 diF (m, 1H), 3.26 (s, 3H), 3.82 (m, 3H), 4.73 (d, 1H),5.52 (s, H), 6.82 (d, 2H), 7.18 (t, 1H), 7.37 (d, 2H), 7.43 (dd, 1H),7.50 (m, 1H), 8.14 (s, 1H), 8.82 (s, 1H) 14 2- —CH₂CH₂OH 2.09 (s, 3H),2.19 (s, 6H), 2.31 438.6 CH₃ (dd, 1H), 2.41 (dd, 1H), 3.58 (brs, 3.H),3.78 (m, 1H), 3.88 (m, 2H), 4.07 (brs, 1H), 4.71 (brs, 1H), 4.80 (brs,1H), 5.17 (brs, 1H), 6.79 (d, 2H), 7.31 (m, 6H), 8.18 (s, 1H), 8.70 (s,1H)

Preparation of Starting Materials for Examples 13 and 14

The starting materials of Formula I for Examples 13 and 14 were preparedusing the procedure of Reference Examples 4 or 6 using the appropriateaniline.

Formula I

Ref Method M/z Ex of Ref Ex R₁ R₂ NMR (MH⁺) 10  4* 2,4-diF CH₃ 3.26(s,3H), 329.3 5.48(s, 1H), 6.64(d, 2H), 7.16(t, 1H), 7.20(d, 2H), 7.46(m,2H), 8.11(s, 1H), 8.69(s, 1H), 9.02(s, 1H). 11 6 2-CH₃ —CH₂CH₂OH 2.07(s,3H), 337.4 3.56(bs, 3H), 4.69(t, 2H), 5.09(bs, 1H), 6.58(d, 2H), 7.14(d,2H), 7.28(m, 4H), 8.12(s, 1H), 8.54(s, 1H), 8.96(s, 1H).*1,2-dichlorobenzene was used as solvent

Example 154-[4-(3-t-Butylamnino-2-hydroxyprorpoxy)anilino]-6-[(N-4,4,4-trifluorobutyl)-2-chloro-5-methylanilino]pyrimidine

4-(4-Hydroxyanilino)-6-[(N-4,4,4-trifluorobutyl)-2-chloro-5-methylanilino]pyrimidine(Reference Example 14, 250 mg, 0.57 mmol) was dissolved in DMSO (2 ml)and K₂CO₃ (160 mg, 1.15 mmol) was added. The resulting suspension wasstirred for 30 mins to give a turquoise solution. Epibromohydrin (0.15ml, 1.7mmol) was added and stirred the solution was stirred overnight.To this green solution was added t-butylamine (1.21 ml, 11.4 mmol) andthe reaction was stirred for 12 hours. DCM (20 ml) and silica (3 g) wereadded. The mixture was evaporated to dryness on high vacuum and thenloaded onto a 10 g Mega Bond Elut column. Eluted with DCM (2×25 ml), 2%NH₃ in MeOH (3×25 ml), 4% NH₃ in MeOH (3×25 ml), 6% NH₃ in MeOH (3×25ml), 10% NH₃ in MeOH (9×25 ml) and product was isolated as a pink/brownoil (280 mg, 86%). M/z 566.7 (MH⁺).

Example 164-[4-(3-Isopropylamino-2-hydroxypropoxy)anilino]-6-(N-4,4,4-trifluorobutyl-2-chloro-5-methylanilino)pyrimidine

The title compound was prepared by the method of Example 15 except thatisopropylamine (0.98 ml, 11.5 mmol) was used instead of t-butylamine togive a pink/brown oil (270 mg, 85%), M/z 552.7 (MH⁺).

Reference Example 12 4-Chloro-6-(2-chloro-5-methylanilino)pyrimidine

Tetramethylene sulphone (10 ml) was added to 4,6-dichloropyrimidine(25.0 g, 170 mmol) and heated to 125° C. 2-Chloro-5-methylaniline (11.90g, 84 mmol) was added portion wise over 20 mins. The reaction mixturewas heated at 125° C. for 2 hours. The reaction was allowed to cool toroom temperature and DCM (200 ml) was added. The mixture was basified topH 9-10 with methanolic ammonia and evaporated onto silica (15 g). Theresidue was purified by column chromatography eluting withEtOAc:isohexane (10:90) to give a white solid (12.25 g, 29%). NMR (300MHz): 2.3 (s, 3H), 6.7 (s, 1H), 7.0 (d, 1H), 7.4 (d, 1H), 7.5 (s, 1H),8.4 (s, 1H), 9.4 (s, 1H); m/z 254 (MH⁺).

Reference Example 134-Chloro-6-[(N-4,4,4-Trifluorobutyl)-2-chloro-5-methylanilino]pyrimidine

4-Chloro-6-(2-chloro-5-methylanilino)pyrimidine (Reference Example 12,12.00 g, 47 mmol) was dissolved in NMP (3 ml) and potassium carbonate(13.11 g, 95 mmol) and 1,1,1-trifluorobutane (11.77 g, 62 mmol) wereadded. The reaction mixture was heated at 50° C. for 3 hours the allowedto cool to room temperature. DCM (10 ml) was added and the mixture wasevaporated onto silica (2 g). The residue was purified by columnchromatography eluting with EtOAc: iso-hexane (10:90) to give acolourless oil (14.14 g, 82%). NMR: 1.8 (m, 2H), 2.3 (m, 5H), 3.8 (brs,1H), 4.0 (brs, 1H), 7.2 (d, 1H) 7.4 (s, 1H), 7.6 (d, 1H), 8.4 (brs, 1H);m/z 364.2 (MH⁺).

Reference Example 144-(4-Hydroxyanilino)-6-[(N-4,4,4-trifluoroburyl)-2-chloro-5-methylanilino]pyrimidine

4-Chloro-6-[(N-4,4,4-trifluorobutyl)-2-chloro-5-methylanilino]pyrimidine(Reference Example 13, 7.00 g, 19 mmol) was suspended in tetramethylenesulphone (15 ml) and p-aminophenol was added (2.0 g, 18 mmol). Thereaction mixture was heated at 160° C. for 90 mins and allowed to coolto room temperature. DCM (50 ml) and silica (10 g) were added and themixture was evaporated to dryness. Purified by MPLC, eluting with DCM,then 2% NH₃ in MeOH to isolate product as white solid (6.51 g, 77%). NMR(300 MHz) 1.8 (m, 2H), 2.2-2.4 (m, 5H), 5.2 (s, 1H), 6.6 (d, 2H), 7.2(d, 2H), 7.3 (d, 1H), 7.35 (s, 1H), 7.5 (d, 1H), 8.2 (s, 1H), 8.6 (s,1H), 9.0 (s, 1H); m/z 437.3 (MH⁺).

Example 174-{4-[3-(N,N-Dimethyl)amino-2-hydroxyproyoxy]anilino}-6-(N-cinnamyl-4-bromoanilino)pyrimidine

4-Chloro-6-[N-cinnamyl-4-bromoanilino]pyrimidine (Reference Example 16,0.38 g, 0.95 mmol) was dissolved in a mixture of NMP (1 ml) andtetramethylene sulphone (1 ml).4-[3-(N,N-Dimethyl)amino-2-hydroxypropoxy]aniline dihydrochloride(Reference Example 21) (0.26 g, 0.92 mmol) was added and the mixtureheated to 160° C. for one hour. After cooling to ambient temperature thebrown solution was partitioned between EtOAc and saturated aqueoussodium bicarbonate solution. The organic laver was washed once with 50%aqueous brine and once with saturated brine. It was then dried overanhydrous sodium sulphate, filtered and evaporated. The residue waspurified by column chromatography [7M NH₃/MeOH (4%): DCM]. Fractionscontaining product were evaporated and the residual gum dissolved inether. This solution was filtered and evaporated to give a foam (0.31 g,57%). NMR: 2.15 (s, 6H), 2.2-2.4 (m, 2H), 3.7-3.9 (m, 3H), 4.65 (d, 2H),4.74 (d, 1H), 5.60 (s, 1H), 6.25-6.5 (m, 2H), 6.8 (d, 2H), 7.16-7.4 (m,9H), 7.63 (d, 2H), 8.2 (s, 1H), 8.8 (s, 1H); m/z 574 [MH⁺].

Examples 18-22

The following compounds were prepared by an analogous method to thatdescribed in Example 17 using the appropriate starting materials. Thestarting materials for Examples 18-20 were prepared by analogy withReference Example 16, the starting materials for Examples 21 and 22 aredescribed in Reference Examples 17 and 18.

Formula A

Ex m/z No R₁ R₂ NMR 300 MHz (MH⁺) 18 2,5-diCl Ph—CH═CH—CH₂— 2.16(s, 6H),2.2-2.4(m, 2H), 3.76(m, 1H), 564 3.85(m, 2H), 4.6(brs, 2H), 4.74(d, 1H),5.42(brs, 1H), 6.35(m, 1H), 6.5(d, 1H), 6.8(d, 2H), 7.3(m, 7H), 7.47(dd,1H), 7.66(m, 2H), 8.2(s, 1H), 8.85(s, 1H), 19 2-Cl-4-Me Ph—CH═CH—CH₂—2.15(s, 6H), 2.2-2.4(m, 5H), 3.7-3.9(m, 3H), 544 4.3(brs, 1H), 4.72(brs,1H), 4.85(brs, 1H), 5.28(brs, 1H), 6.25-6.49(m, 2H), 6.78(d, 2H),7.15-7.4(m, 9H), 7.46(s, 1H), 8.2(s, 1H), 8.8(s, 1H) 20 2,4-diFPh—CH═CH—CH₂— 2.16(s, 6H), 2.2-2.4(m, 2H), 3.77(m, 1H), 3.90(m, 2H), 5324.57(d, 2H), 4.72(brs, 1H), 5.50(s, 1H), 6.24-6.36(m, 1H), 6.47(d, 1H),6.8(d, 2H), 7.14-7.46(m, 9H), 7.53(m, 1H), 8.18(s, 1H), 8.82(s, 1H) 212-Cl-5-Me CF₃—(CH₂)₃— 1.76(m, 2H), 2.15(s, 6H), 2.2-2.4(m, 7H), 5383.7-4.1(m, 5H), 4.72(brs, 1H), 5.18(s, 1H), 6.78(d, 2H), 7.24(dd, 1H),7.34(m, 3H), 7.53(d, 1H), 8.20(s, 1H), 8.77(s, 1H) 22* 2-Cl-5-MeBr—CH═CH—CH₂— 2.16(s, 6H), 2.2-2.4(m, 5H), 3.7-3.9(m, 3H), 546 4.73(brs,1H), 5.26(brs, 1H), 6.26-6.54(m, 2H), 6.78(d, 2H), 7.2-7.37(m, 4H),7.50(d, 1H), 8.20(s, 1H), 8.80(s, 1H) *The reaction was carried out at100° C. for four hours.

Reference Example 15 4-Chloro-6-(4-bromoanilino)pyrimidine

4,6-Dichloropyrimidine (3.0 g, 20 mmol) was mixed with 4-bromoaniline(3.3 g, 19 mmol) and heated to 125° C. for two hours in tetramethylenesulphone. After cooling the reaction mixture was partitioned betweensaturated aqueous sodium bicarbonate solution and EtOAc. The organicportion was washed, dried over sodium sulphate, filtered and evaporated.The residue was purified by column chromatography (EtOAc (20%):isohexane) to yield a solid (0.6 g, 11%). M/z 284 (MH)⁺.

Reference Example 16 4-Chloro-6-(N-cinnamyl-4-bromoanilino)pyrimidine

4-Chloro-6-(4-bromoanilino)pyrimidine (Reference Example 15) (0.3 g, 1.0mmol) and cinnamyl bromide (0.23 g, 1.2 mmol) were dissolved in NMP (2ml). Caesium carbonate (0.5 g, 1.5 mmol) was added and the mixture washeated to 70° C. for one hour. Following an aqueous work-up withextraction into EtOAc the product was obtained by column chromatography(EtOAc (4%): isohexane) (0.4 g, 94%). M/z 400 (NH)⁺.

Reference Example 174-Chloro-6-[N-(4,4,4-trifluorobutyl)-2-chloro-5-methylanilino]pyrimidine

4-Chloro-6-(2-chloro-5-methylanilino)pyrimidine (Reference Example 12)(0.28 g, 1.1 mmol) and 1,1,1-trifluoro-4-bromobutane (0.32 g, 1.67 mmol)were dissolved in NMP (2 ml). Anhydrous potassium carbonate (0.31 g, 2.2mmol) was added and the mixture heated to 50° C. for three hours.Following an aqueous work-up the product was obtained by columnchromatography on silica gel using EtOAc-isohexane mixtures. (0.3 g,75%). M/z 364 (MH)⁺.

Reference Example 184-Chloro-6-[N-(3-bromoallyl)-2-chloro-5-methylanilino]pyrimidine

4-Chloro-6-(2-chloro-5-methylanilino)pyrimidine (Reference Example 12)(0.5 g, 1.97 mmol) and 1,3-dibromopropene [cis/trans mixture] (0.6 g,3.0 mmol) were dissolved in NMP (2 ml). Anhydrous potassium carbonate(0.54 g, 4 mmol) was added and the mixture stirred at room temperaturefor seventeen hours. After aqueous work-up the product was obtained bycolumn chromatography on silica gel using EtOAc/isohexane mixtures (0.68g, 93%). M/z 372 (MH)⁺.

Reference Example 19 1-(4-Nitrophenoxy)-2,3-epoxypropane

1-(4-Nitrophenoxy)-2,3-epoxypropane was prepared by an analogous methodto that described by Zhen-Zhong Lui et. al. in Synthetic Communications(1994), 24, 833-838.

4-Nitrophenol (4.0 g), anhydrous potassium carbonate (8.0 g) andtetrabutylamnnonium bromide (0.4 g) were mixed with epibromohydrin (10ml). The reaction mixture was heated at 100° C. for 1 hour. Aftercooling to ambient temperature, the reaction mixture was diluted withEtOAc and filtered. The filtrate was evaporated to dryness and theresidue was co-distilled twice with toluene. The resulting oil waspurified by column chromatography and eluted with EtOH (1.0%):DCM togive the title product on evaporation as an oil that crystallised (4.36g, 77.7%). NMR (CDCl₃, 300 MHz): 2.78 (m, 1H), 2.95 (m, 1H), 3.38 (m,1H), 4.02 (dd, 1H), 4.38 (dd, 1H), 7.00 (d, 2H), 8.20 (d, 2H); m/z:(ES⁺) 196 (MH⁺).

Reference Example 203-(N,N-Dimethyl)amino-2-hydroxy-1-(4-nitrophenoxy)propane

1-(4-Nitrophenoxy)-2,3-epoxypropane (Reference Example 19, 4.3 g) wasdissolved in methanol (30 ml) and DMF (10 ml). Dimethylamine (2Msolution in methanol, 17 ml) was added and the mixture was stirred atambient temperature overnight. The reaction mixture was evaporated todryness and the residue was dissolved in saturated sodium bicarbonatesolution and EtOAc. The EtOAc layer was separated and washed twice withsaturated brine, dried over anhydrous sodium sulphate, filtered andevaporated to give the title product as an oil that slowly crystallisedunder high vacuum (4.79 g, 89.9%). NMR (CDCl₃, 300 MHz): 2.33 (s, 6H),2.98 (m, 1H), 2.54 (m, 1H), 4.00 (m, 3 H), 7.00 (d, 2H), 8.20 (d, 2H);m/z: (ES⁺) 241 (MH⁺).

Reference Example 21 4-[3-(N,N-Dimethyl)amino-2-hydroxyoroloxy]aniline

3-(N,N-Dimethyl)amino-2-hydroxy-3-(4-nitrophenoxy)propane (ReferenceExample 20, 3.75 g) was dissolved in EtOH (40 ml). Under an atmosphereof nitrogen, 10% palladium-on-carbon (0.4 g) was added. The nitrogenatmosphere was replaced by one of hydrogen and the reaction mixture wasstirred overnight. The catalyst was removed by filtration throughdiatomaceous earth and the filtrate was evaporated to dryness. Theresidue was dissolved in diethyl ether containing a small amount ofisopropanol and hydrogen chloride solution (1M in ether, 16 ml) wasadded. The ether was evaporated and the solid residue was suspended inisopropanol. This mixture was heated on a steam bath for several minutesthen allowed to cool to ambient temperature. The resulting powder wascollected by filtration, washed with isopropanol, ether and dried togive the title product (3.04 g, 72.4%). NMR (300 MHz): 2.80 (s, 6H),3.15 (m, 2H), 3.88 (m, 2H), 4.25 (m, 1H), 5.93 (br S, 1H), 6.88 (m, 4H);m/z: (ES⁺) 211 (MH⁺); EA: C₁₁H₁₃N₂O₂.1.6 HCl requires C; 49.2, H; 7.4,N; 10.4, Cl; 21.7%: found: C; 49.2, H; 7.2, N; 10.1; Cl; 19.1%.

Example 23

The following illustrate representative pharmaceutical dosage formscontaining the compound of formula (I), or a pharmaceutically-acceptablesalt or in-vivo hydrolysable ester thereof (hereafter compound X), fortherapeutic or prophylactic use in humans:

(a): Tablet I mg/tablet Compound X 100 Lactose Ph. Eur 182.75Croscarmellose sodium 12.0 Maize starch paste (5% w/v paste) 2.25Magnesium stearate 3.0 (b): Tablet II mg/tablet Compound X 50 LactosePh. Eur 223.75 Croscarmellose sodium 6.0 Maize starch 15.0Polyvinylpyrrolidone 2.25 (5% w/v paste) Magnesium stearate 3.0 (c):Tablet III mg/tablet Compound X 1.0 Lactose Ph. Eur 93.25 Croscarmellosesodium 4.0 Maize starch paste (5% w/v paste) 0.75 Magnesium stearate 1.0(d): Capsule mg/capsule Compound X 10 Lactose Ph. Eur 488.5 Magnesiumstearate 1.5 (e): Injection I (50 mg/ml) Compound X 5.0% w/v 1M Sodiumhydroxide solution 15.0% v/v 0.1 M Hydrochloric acid (to adjust pH to7.6) Polyethylene glycol 400 4.5% w/v Water for injection to 100% (f):Injection II 10 mg/ml Compound X 1.0% w/v Sodium phosphate BP 3.6% w/v0.1 M Sodium hydroxide solution 15.0% v/v Water for injection to 100%(g): Injection III (1 mg/ml, buffered to pH 6) Compound X 0.1% w/vSodium phosphate BP 2.26% w/v Citric acid 0.38% w/v Polyethylene glycol400 3.5% w/v Water for injection to 100% Note The above formulations maybe obtained by conventional procedures well known in the pharmaceuticalart. The tablets (a)-(c) may be enteric coated by conventional means,for example to provide a coating of cellulose acetate phthalate.

What is claimed is:
 1. A pyrimidine compound of the formula (I)

wherein R¹ is selected from (1-6C)alkyl [substituted by one or twosubstituents independently selected from halo, amino, (1-4C)alkylamino,di-[(1-4C)alkyl]amino, hydroxy, cyano, (1-4C)alkoxy,(1-4C)alkoxycarbonyl, carbamoyl, —NHCO(1-4C)alkyl, trifluoromethyl,phenylthio, phenoxy, pyridyl, morpholino], benzyl, 2-phenylethyl,(3-5C)alkenyl [optionally substituted by up to three halo substituents,or by one trifluoromethyl substituent, or one phenyl substituent],N-phthalimido-(1-4C)alkyl, (3-5C)alkynyl [optionally substituted by onephenyl substituent] and (3-6C)cycloalkyl-(1-6C)alkyl; wherein any phenylor benzyl group in R¹ is optionally substituted by up to threesubstituents independently selected from halogeno, hydroxy, nitro,amino, (1-3C)alkylamino, di-[(1-3C)alkyl]amino, cyano, trifluoromethyl,(1-3C)alkyl [optionally substituted by 1 or 2 substituents independentlyselected from halogeno, cyano, amino, (1-3C)alkylamino,di-[(1-3C)alkyl]amino, hydroxy and trifluoromethyl], (3-5C)alkenyl[optionally substituted by up to three halo substituents, or by onetrifluoromethyl substituent], (3-5C)alkynyl, (1-3C)alkoxy, —SH,—S-(1-3C)alkyl, carboxy, (1-3C)alkoxycarbonyl; Q₁ and Q₂ areindependently selected from phenyl, naphthyl, indanyl and1,2,3,4-tetrahydronaphthyl; and one or both of Q₁ and Q₂ bears on anyavailable carbon atom bne substituent of the formula (Ia) and Q₂ mayoptionally bear on any available carbon atom further substituents of theformula (Ia)

 [provided that when present in Q₁ the substituent of formula (Ia) isnot adjacent to the —NH— link]; wherein X is CH₂, O, S, NH or NRx[wherein Rx is (1-4C)alkyl, optionally substituted by one substituentselected from halo, amino, cyano, (1-4C)alkoxy or hydroxy]; Y is H or asdefined for Z; Z is OH, SH, NH₂, (1-4C)alkoxy, (1-4C)alkylthio,—NH(1-4C)alkyl, —N[(1-4C)alkyl]₂, —NH-(3-8C)cycloalkyl, pyrrolidin-1-yl,piperidin-1-yl, piperazin-1-yl [optionally substituted in the 4-positionby (1-4C)alkyl or (1-4C)alkanoyl], morpholino or thiomorpholino; nis 1,2 or 3; m is 1, 2 or 3; and Q₁ and Q₂ may each optionally andindependently bear on any available carbon atom up to four substituentsindependently selected from halogeno, hydroxy, thio, nitro, carboxy,cyano, (2-4C)alkenyl [optionally substituted by up to three halosubstituents, or by one trifluoromethyl substituent], (2-4C)alkynyl,(1-5C)alkanoyl, (1-4C)alkoxycarbonyl, (1-6C)alkyl, hydroxy-(1-6C)alkyl,fluoro-(1-4C)alkyl, amino-(1-3C)alkyl, (1-4C)alkylamino-(1-3C)alkyl,di-[(1-4C)alkyl]amino-(1-3C)alkyl, cyano-(1-4C)alkyl,2-4C)alkanoyloxy-(1-4C)-alkyl, (1-4C)alkoxy-(1-3C)alkyl,carboxy-(1-4C)alkyl, (1-4C)alkoxycarbonyl-(1-4C)alkyl,carbamoyl-(1-4C)alkyl, N-(1-4C)alkylcarbamoyl-(1-4C)alkyl,N,N-di-[(1-4C)alkyl]-carbamoyl-(1-4C)alkyl, pyrrolidin-1-yl-(1-3C)alkyl,piperidin-1-yl-(1-3C)alkyl, piperazin-1-yl-(1-3C)alkyl,morpholino-(1-3C)alkyl, thiomorpholino-(1-3C)alkyl, piperazin-1-yl,morpholino, thiomorpholino, (1-4C)alkoxy, cyano-(1-4C)alkoxy,carbamoyl-(1-4C)alkoxy, N-(1-4C)alkylcarbamoyl-(1-4C)alkoxy,N,N-di-[(1-4C)alkyl]-carbamoyl-(1-4C)alkoxy, 2-aminoethoxy,2-(1-4C)alkylaminoethoxy, 2-di-[(1-4C)alkyl]aminoethoxy,(1-4C)alkoxycarbonyl-(1-4C)alkoxy, halogeno-(1-4C)alkoxy,2-hydroxyethoxy, (2-4C)alkanoyloxy-(2-4C)alkoxy, 2-(1-4C)alkoxyethoxy,carboxy-(1-4C)alkoxy, (3-5C)alkenyloxy, (3-5C)alkynyloxy,(1-4C)alkylthio, (1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl,hydroxy-(2-4C)alkylthio, hydroxy-(2-4C)alkylsulphinyl,hydroxy-(2-4C)alkylsulphonyl, ureido (H₂N—CO—NH—), (1-4C)alkylNH—CO—NH—,di-[(1-4C)alkyl]N—CO—NH—, (1-4C)alkylNH—CO—N[(1-4C)alkyl]-,di-[(1-4C)alkyl]N—CO—N[(1-4C)alkyl]-, carbamoyl,N-[(1-4C)alkyl]carbamoyl, N,N-di-[(1-4C)alkyl]carbamoyl, amino,(1-4C)alkylamino, di-[(1-4C)alkyl]amino, (2-4C)alkanoylamino, and alsoindependently, or in addition to, the above optional substituents, Q₁and/or Q₂ may optionally bear on any available carbon atom up to twofurther substituents independently selected from (3-8C)cycloalkyl,phenyl-(1-4C)alkyl, phenyl-(1-4C)alkoxy, phenylthio, phenyl, naphthyl,benzoyl, phenoxy, benzimidazol-2-yl and a 5- or 6-membered aromaticheterocycle (linked via a ring carbon atom and having one to threeheteroatoms independently selected from oxygen, sulphur and nitrogen);wherein said naphthyl, phenyl, benzoyl, 5- or 6-membered aromaticheterocyclic substituents and the phenyl group in saidphenyl-(1-4C)alkyl, phenylthio, phenoxy and phenyl-(1-4C)alkoxysubstituents may optionally bear up to five substituents independentlyselected from halogeno, (1-4C)alkyl and (1-4C)alkoxy; or apharmaceutically-acceptable salt or in-vivo-hydrolysable ester thereof.2. A pyrimidine compound of the formula (I) as claimed in claim 1,wherein R¹ is benzyl [optionally substituted by up to three substituentsindependently selected from halogeno, hydroxy, nitro, amino,(1-3C)alkylamino, di-[(1-3C)alkyl]amino, cyano, trifluoromethyl,(1-3C)alkyl, (1-3C)alkoxy, —SH, —S-(1-3C)alkyl, carboxy and(1-3C)alkoxycarbonyl], (3-5C)alkynyl, (3-6C)cycloalkyl-(1-6C)alkyl,(1-4C)alkyl [substituted by one or two substituents independentlyselected from hydroxy, amino, halo, trifluoromethyl and cyano] or(3-5C)alkenyl substituted by one to three halo groups or one phenylsubstituent; Q₁ and Q₂ are independently selected from phenyl, naphthyl,indanyl and 1,2,3,4-tetrahydronaphthyl; and one or both of Q₁ and Q₂bears on any available carbon atom one substituent of the formula (Ia)and Q₂ may optionally bear on any available carbon atom furthersubstituents of the formula (Ia) [provided that when present in Q₁ thesubstituent of formula (Ia) is not adjacent to the —NH— link]; X is CH₂,O, S, NH or NRx [wherein Rx is (1-4C)alkyl, optionally substituted byone substituent selected from halo, amino, cyano, (1-4C)alkoxy orhydroxy]; Y is H or as defined for Z; Z is OH, SH, NH₂, (1-4C)alkoxy,(1-4C)alkylthio, —NH(1-4C)alkyl, —N[(1-4C)alkyl]₂, —NH-(3-8C)cycloalkyl,pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl [optionally substitutedin the 4-position by (1-4C)alkyl or (1-4C)alkanoyl], morpholino orthiomorpholino; n is 1, 2 or 3; m is 1, 2 or 3; and Q₁ and Q₂ may eachoptionally and independently bear on any available carbon atom up tofour substituents independently selected from halogeno, hydroxy, thio,nitro, carboxy, cyano, (2-4C)alkenyl [optionally substituted by up tothree halo substituents, or by one trifluoromethyl substituent],(2-4C)alkynyl, (1-5C)alkanoyl, (1-4C)alkoxycarbonyl, (1-6C)alkyl,hydroxy-(1-6C)alkyl, fluoro-(1-4C)alkyl, amino-(1-3C)alkyl,(1-4C)alkylamino-(1-3C)alkyl, di-[(1-4C)alkyl]amino-(1-3C)alkyl,cyano-(1-4C)alkyl, (2-4C)alkanoyloxy-(1-4C)-alkyl,(1-4C)alkoxy-(1-3C)alkyl, carboxy-(1-4C)alkyl,(1-4C)alkoxycarbonyl-(1-4C)alkyl, carbamoyl-(1-4C)alkyl,N-(1-4C)alkylcarbamoyl-(1-4C)alkyl,N,N-di-[(1-4C)alkyl]-carbamoyl-(1-4C)alkyl, pyrrolidin-1-yl-(1-3C)alkyl,piperidin-1-yl-(1-3C)alkyl, piperazin-1-yl-(1-3C)alkyl,morpholino-(1-3C)alkyl, thiomorpholino-(1-3C)alkyl, piperazin-1-yl,morpholino, thiomorpholino, (1-4C)alkoxy, cyano-(1-4C)alkoxy,carbamoyl-(1-4C)alkoxy, N-(1-4C)alkylcarbamoyl-(1-4C)alkoxy,N,N-di-[(1-4C)alkyl]-carbamoyl-(1-4C)alkoxy, 2-aminoethoxy,2-(1-4C)alkylaminoethoxy, 2-di-[(1-4C)alkyl]aminoethoxy,(1-4C)alkoxycarbonyl-(1-4C)alkoxy, halogeno-(1-4C)alkoxy,2-hydroxyethoxy, (2-4C)alkanoyloxy-(2-4C)alkoxy, 2-(1-4C)alkoxyethoxy,carboxy-(1-4C)alkoxy, (3-5C)alkenyloxy, (3-5C)alkynyloxy,(1-4C)alkylthio, (1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl,hydroxy-(2-4C)alkylthio, hydroxy-(2-4C)alkylsulphinyl,hydroxy-(2-4C)alkylsulphonyl, ureido (H₂N—CO—NH—), (1-4C)alkylNH—CO—NH—,di-[(1-4C)alkyl]N—CO—NH—, (1-4C)alkylNH—CO—N[(1-4C)alkyl]-,di-[(1-4C)alkyl]N—CO—N[(1-4C)alkyl]-, carbamoyl,N-[(1-4C)alkyl]carbamoyl, N,N-di-[(1-4C)alkyl]carbamoyl, amino,(1-4C)alkylamino, di-[(1-4C)alkyl]amino, (2-4C)alkanoylamino, and alsoindependently, or in addition to, the above optional substituents, Q₁and/or Q₂ may optionally bear on any available carbon atom up to twofurther substituents independently selected from (3-8C)cycloalkyl,phenyl-(1-4C)alkyl, phenyl-(1-4C)alkoxy, phenylthio, phenyl, naphthyl,benzoyl, phenoxy, benzimidazol-2-yl and a 5- or 6-membered aromaticheterocycle (linked via a ring carbon atom and having one to threeheteroatoms independently selected from oxygen, sulphur and nitrogen);wherein said naphthyl, phenyl, benzoyl, 5- or 6-membered aromaticheterocyclic substituents and the phenyl group in saidphenyl-(1-4C)alkyl, phenylthio, phenoxy and phenyl-(1-4C)alkoxysubstituents may optionally bear up to five substituents independentlyselected from halogeno, (1-4C)alkyl and (1-4C)alkoxy; or apharmaceutically-acceptable salt or in-vivo-hydrolysable ester thereof.3. A pyrimidine compound of the formula (I) as claimed in claim 1,wherein R¹ is benzyl [optionally substituted by one (1-3C)alkoxysubstituent], (3-5C)alkynyl, (3-6C)cycloalkyl-(1-6C)alkyl, (1-4C)alkyl[substituted by one or two substituents independently selected fromhydroxy, amino, halo, trifluoromethyl and cyano] or (3-5C)alkenylsubstituted by one to three halo groups or one phenyl substituent; Q₁and Q₂ are independently selected from phenyl or indanyl; and one orboth of Q₁ and Q₂ bears on any available carbon atom one substituent ofthe formula (Ia) and Q₂ may optionally bear on any available carbon atomfurther substituents of the formula (Ia) [provided that when present inQ₁ the substituent of formula (Ia) is not adjacent to the —NH— link]; Xis CH₂, O, S, NH or NRx [wherein Rx is (1-4C)alkyl, optionallysubstituted by one substituent selected from halo, amino, cyano,(1-4C)alkoxy or hydroxy]; Y is H or as defined for Z; Z is OH, SH, NH₂,(1-4C)alkoxy, (1-4C)alkylthio, —NH(1-4C)alkyl, —N[(1-4C)alkyl]₂,—NH-(3-8C)cycloalkyl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl[optionally substituted in the 4-position by (1-4C)alkyl or(1-4C)alkanoyl], morpholino or thiomorpholino; n is 1, 2 or 3; m is 1, 2or 3; and Q₁ may optionally bear on any available carbon atom up to foursubstituents independently selected from halogeno, thio, nitro, carboxy,cyano, (2-4C)alkenyl [optionally substituted by up to three halosubstituents, or by one trifluoromethyl substituent], (2-4C)alkynyl,(1-5C)alkanoyl, (1-4C)alkoxycarbonyl, (1-6C)alkyl, hydroxy-(1-6C)alkyl,fluoro-(1-4C)alkyl, amino, (1-4C)alkylamino, di-[(1-4C)alkyl]amino,(2-4C)alkanoylamino; and Q₂ may optionally bear on any available carbonatom up to four substituents independently selected from halogeno,hydroxy, thio, nitro, carboxy, cyano, (2-4C)alkenyl [optionallysubstituted by up to three halo substituents, or by one trifluoromethylsubstituent], (2-4C)alkynyl, (1-5C)alkanoyl, (1-4C)alkoxycarbonyl,(1-6C)alkyl, hydroxy-(1-6C)alkyl, fluoro-(1-4C)alkyl, amino,(1-4C)alkylamino, di-[(1-4C)alkyl]amino, (2-4C)alkanoylamino, and alsoindependently, or in addition to, the above optional substituents, Q₂may optionally bear on any available carbon atom up to two furthersubstituents independently selected from phenylthio, phenyl, phenoxy andbenzimidazol-2-yl; or a pharmaceutically-acceptable salt orin-vivo-hydrolysable ester thereof.
 4. A pyrimidine compound of theformula (I) as claimed in claim 1, wherein R¹ is benzyl [optionallysubstituted by one (1-3C)alkoxy substituent], (3-5C)alkynyl,(3-6C)cycloalkyl-(1-6C)alkyl, (1-4C)alkyl [substituted by one or twosubstituents independently selected from hydroxy, amino, halo,trifluoromethyl and cyano] or (3-5C)alkenyl substituted by one to threehalo groups or one phenyl substituent; Q₁ and Q₂ are independentlyselected from phenyl or indan-5-yl; and one or both of Q₁ and Q₂ bearson any available carbon atom one substituent of the formula (Ia) and Q₂may optionally bear on any available carbon atom further substituents ofthe formula (Ia) [provided that when present in Q₁ the substituent offormula (Ia)is not adjacent to the —NH— link]; X is O; Y is H or OH; Zis —NH(1-4C)alkyl, -N[(1-4C)alkyl]₂, —NH-(3-8C)cycloalkyl,pyrrolidin-1-yl or piperazin-1-yl [optionally substituted in the4-position by (1-4C)alkyl or (1-4C)alkanoyl]; n is 1 or 2 and m is 1 or2; and Q₁ may optionally bear on any available carbon atom up to foursubstituents independently selected from halogeno, thio, nitro, carboxy,cyano, (2-4C)alkenyl [optionally substituted by up to three halosubstituents, or by one trifluoromethyl substituent], (2-4C)alkynyl,(1-5C)alkanoyl, (1-4C)alkoxycarbonyl, (1-6C)alkyl, hydroxy-(1-6C)alkyl,fluoro-(1-4C)alkyl, amino, (1-4C)alkylamino, di-[(1-4C)alkyl]amino,(2-4C)alkanoylamino; and Q₂ may optionally bear on any available carbonatom up to four substituents independently selected from halogeno,hydroxy, thio, nitro, carboxy, cyano, (2-4C)alkenyl [optionallysubstituted by up to three halo substituents, or by one trifluoromethylsubstituent], (2-4C)alkynyl, (1-5C)alkanoyl, (1-4C)alkoxycarbonyl,(1-6C)alkyl, hydroxy-(1-6C)alkyl, fluoro-(1-4C)alkyl, amino,(1-4C)alkylamino, di-[(1-4C)alkyl]amino, (2-4C)alkanoylamino, and alsoindependently, or in addition to, the above optional substituents, Q₂may optionally bear on any available carbon atom up to two furthersubstituents independently selected from phenylthio, phenyl, phenoxy andbenzimidazol-2-yl; or a pharmaceutically-acceptable salt orin-vivo-hydrolysable ester thereof.
 5. A pyrimidine compound of theformula (I) as claimed in claim 1, wherein R¹ is cyanomethyl,—CH₂CH═CHBr, —CH₂CH₂CH₂CF₃ or —CH₂CH═CH-phenyl; Q₁ and Q₂ areindependently selected from phenyl or indan-5-yl; and one or both of Q₁and Q₂ bears on any available carbon atom one substituent of the formula(Ia) and Q₂ may optionally bear on any available carbon atom furthersubstituents of the formula (Ia) [provided that when.present in Q₁ thesubstituent of formula (Ia) is not adjacent to the —NH— link]; X is O; Yis H or OH; Z is —NH(1-4C)alkyl, —N[(1-4C)alkyl]₂, —NH-(3-8C)cycloalkyl,pyrrolidin-1-yl or piperazin-1-yl [optionally substituted in the4-position by (1-4C)alkyl or (1-4C)alkanoyl]; n is 1 or 2 and m is 1 or2; and Q₁ and/or Q₂ may independently and optionally bear on anyavailable carbon atom up to four substituents independently selectedfrom halogeno, hydroxy, thio, nitro, carboxy, cyano, (2-4C)alkenyl[optionally substituted by up to three halo substituents, or by onetrifluoromethyl substituent], (2-4C)alkynyl, (1-5C)alkanoyl,(1-4C)alkoxycarbonyl, (1-6C)alkyl, hydroxy-(1-6C)alkyl,fluoro-(1-4C)alkyl, amino, (1-4C)alkylamino, di-[(1-4C)alkyl]amino,(2-4C)alkanoylamino, and also independently, or in addition to, theabove optional substituents, Q₁ and/or Q₂ may optionally bear on anyavailable carbon atom up to two further substituents independentlyselected from phenylthio, phenyl, phenoxy and benzimidazol-2-yl; or apharmaceutically-acceptable salt or in-vivo-hydrolysable ester thereof.6. A pyrimidine compound of the formula (I) as claimed in claim 1,wherein R¹ is cyanomethyl, —CH₂CH═CHBr, —CH₂CH₂CH₂CF₃ or—CH₂CH═CH—phenyl; Q₁ and Q₂ are both phenyl; Q₁ bears on any availablecarbon atom one substituent of the formula (Ia) [provided that thesubstituent of formula (Ia) is not adjacent to the —NH— link]; X is O; Yis H or OH; Z is —NH(1-4C)alkyl or —N[(1-4C)alkyl]₂; n is 1 or 2and m is1 or2; and Q₁ and/or Q₂ may independently and optionally bear on anyavailable carbon atom up to four substituents independently selectedfrom halogeno, hydroxy, thio, nitro, carboxy, cyano, (2-4C)alkenyl[optionally substituted by up to three halo substituents, or by onetrifluoromethyl substituent], (2-4C)alkynyl, (1-5C)alkanoyl,(1-4C)alkoxycarbonyl, (1-6C)alkyl, hydroxy-(1-6C)alkyl,fluoro-(1-4C)alkyl, amino, (1-4C)alkylamino, di-[(1-4C)alkyl]amino,(2-4C)alkanoylamino, and also independently, or in addition to, theabove optional substituents, Q₁ and/or Q₂ may optionally bear on anyavailable carbon atom up to two further substituents independentlyselected from phenylthio, phenyl, phenoxy and benzimidazol-2-yl; or apharmaceutically-acceptable salt or in-vivo-hydrolysable ester thereof.7. A pyrimidine compound of the formula (I) as claimed in claim 1,wherein R¹ is cyanomethyl, —CH₂CH═CHBr, —CH₂CH₂CH₂CF₃ or—CH₂CH═CH-phenyl; Q₁ and Q₂ are both phenyl; Q₁ bears on any availablecarbon atom one substituent of the formula (Ia) [provided that thesubstituent of formula (Ia) is not adjacent to the —NH— link]; X is O; Yis OH; Z is —NH(1-4C)alkyl or —N[(1-4C)alkyl]₂; n is 1 or 2 and m is 1or 2; and Q₂ optionally bears on any available carbon atom up to twosubstituents independently selected from halogeno, hydroxy, thio, nitro,carboxy, cyano, (2-4C)alkenyl [optionally substituted by up to threehalo substituents, or by one trifluoromethyl substituent],(2-4C)alkynyl, (1-5C)alkanoyl, (1-4C)alkoxycarbonyl, (1-6C)alkyl,hydroxy-(1-6C)alkyl, fluoro-(1-4C)alkyl, amino, (1-4C)alkylamino,di-[(1-4C)alkyl]amino, (2-4C)alkanoylamino;. or apharmaceutically-acceptable salt or in-vivo-hydrolysable ester thereof.8. A pyrimidine compound of the formula (I) as claimed in claim 1,being:4-{4-[3-(N,N-Dimethyl)amino-2-hydroxy-propoxy]anilino}-6-(N-cyanomethyl-2-bromo-4-methylanilino)pyrimidine;4-{4-[3-(N,N-Dimethyl)amino-2-hydroxy-propoxy]anilino}-6-(N-cyanomethyl-2-chloro-5-methylanilino)pyrimidine;4-{4-[3-(N,N-Dimethyl)amino-2-hydroxy-propoxy]anilino}-6-(N-cyanomethyl-2,5-dichloroanilino)pyrimidine;4-{4-[3-(N,N-Dimethyl)amino-2-hydroxy-propoxy]anilino}-6-(N-(4,4,4-trifluorobutyl)-2,5-dichloroanilino)pyrimidine;4-{4-[3-(N,N-Dimethyl)amino-2-hydroxy-propoxy]anilino}-6-(N-(3-phenylprop-2-enyl)-2,4-difluoroanilino)pyrimidine;4-{4-[3-(N,N-Dimethyl)amino-2-hydroxy-propoxy]anilino}-6-(N-(3-phenylprop-2-enyl)-2-chloro-4-methylanilino)pyrimidine;or a pharmaceutically-acceptable salt or in-vivo hydrolysable esterthereof.
 9. A process for the preparation of a compound of the formula(I) as claimed in claim 1, which comprises of a) to i): a) reacting apyrimidine of formula (II):

 wherein L is a displaceable group, with a compound of formula (III):

b) reaction of a pyrimidine of formula (IV):

 wherein L is a displaceable group, with a compound of formula (V):

c) reacting a pyrimidine of formula (VI):

 with a compound of formula (VII) R¹—L  (VII) wherein L is adisplaceable group; d) for compounds of formula (I) where n=1, 2 or 3;m=1 and Y is OH, NH₂ or SH, reaction of a 3-membered heteroalkyl ring offormula (VIII):

 wherein A is O, S or NH; with a nucleophile of formula (IX): Z—D  (IX) wherein D is H or a suitable counter-ion; e) for compounds of formula(I) where X is oxygen, by reaction of an alcohol of formula (X)

 with an alcohol of formula (XI):

f) for compounds of formula (I) wherein X is CH₂, O, NH or S; Y is OHand m is 2 or 3: reaction of a compound of formula (XII):

 wherein —OLg is a leaving group; with a nucleophile of formula Z—D (IX)wherein D is H or a suitable counter-ion; g) for compounds of formula(I) wherein X is CH₂, O, NH or S; Y is H; n is 1, 2 or 3 and m is 1, 2or 3: reaction of a compound of formula (XIII):

 wherein —OLg is a leaving group; with a nucleophile of formula Z—D (IX)wherein D is H or a suitable counter-ion; h) for compounds of formula(I) wherein X is O, NH or S; Y is H; n is 1, 2 or 3 and m is 1, 2 or 3:reaction of a compound of formula (XIV) with a compound of formula (XV):

 or i) for compounds of formula (I) in which Z is SH, by conversion of athioacetate group in a corresponding compound; and thereafter ifnecessary: (i) converting a compound of the formula.(I) into anothercompound of the formula (I); (ii) removing any protecting groups; (iii)forming a pharmaceutically acceptable salt or in vivo hydrolysableester; wherein L is a displaceable group and D is hydrogen or acounter-ion.
 10. A pharmaceutical composition which comprises a compoundof the formula (I) as claimed in any one of claims 1 to 8, or apharmaceutically-acceptable salt or an in-vivo hydrolysable esterthereof, and a pharmaceutically-acceptable diluent or carrier.
 11. Amethod for producing an anti-cancer effect in a warm blooded animalwhich comprises administering to said animalan effective amount of acompound of the formula (I) as claimed in any one of claims 1 to 8, or apharmaceutically-acceptable salt, or in-vivo hydrolysable ester thereof.